Piperidylcarboxamide derivatives and their use in the treatment of tachykinin-mediated diseases

ABSTRACT

The present invention relates to piperidine derivatives of formula (I): 
                         
wherein R, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , X, Y, m and n are as defined herein; and pharmaceutically acceptable salts and solvates thereof; the process for their preparation and their use in the treatment of conditions mediated by tachykinins.

CROSS REFERENCES TO RELATED APPLICATIONS

This application is a 371 Application of PCT/GB03/00499, filed 5 Feb.2003, which claims priority to GB Application Serial Nos. 0203021.1 and0203019.5, both filed 8 Feb. 2002.

The present invention relates to piperidine derivatives, to processesfor their preparation, to pharmaceutical compositions containing themand to their medical use.

In particular the invention relates to novel compounds which are potentand specific antagonists of tachykinins, including substance P and otherneurokinins.

WO 99/37304 discloses interalia some 2-aryl-1,4-disubstituted piperidinederivatives as factor Xa inhibitors. Such compounds are useful asinhibitors of blood coagulation in mammalian species.

WO 97/16440 and WO 02/32867 disclose certain 2-aryl-1,4-disubstitutedpiperidines as NK1 antagonists.

However, in the above cited documents there is neither disclosure norsuggestion of any compound as claimed herein.

Thus, the present invention provides compounds of formula (I)

wherein

-   R represents halogen or C₁₋₄ alkyl;-   R₁ represents hydrogen or C₁₋₄ alkyl;-   R₂ represents hydrogen, C₁₋₄ alkyl or R₂ together with R₃ represents    C₃₋₇ cycloalkyl;-   R₃ represents hydrogen, C₁₋₄ alkyl, C₃₋₇ cycloalkyl or C₃₋₆ alkenyl;    or R₁ and R₃ together with nitrogen and carbon atom to which they    are attached respectively represent a 5 to 6 membered heterocyclic    group;-   R₄ represents trifluoromethyl, C₁₋₄ alkyl, C₁₋₄ alkoxy,    trifluoromethoxy or halogen;-   R₅ is hydrogen and R₆ is NR₇R₈ or R₅ is NR₈R₉ and R₆ is hydrogen;-   R₇ represents hydrogen or C₁₋₄ alkyl or R₇ and R₈ together with    nitrogen to which they are attached are a saturated 5 to 7 membered    heterocyclic group containing oxygen;-   R₈ represents hydrogen, phenyl, C₃₋₇ cycloalkyl, (CH2)pC(O)NR₁₀R₁₁,    a saturated 5 to 7 membered heterocyclic group containing 1 to 3    heteroatoms selected from oxygen, sulphur and nitrogen and    optionally substituted by C₁₋₄ alkyl, S(O)₂C₁₋₄ alkyl or C(O)C₁₋₄    alkyl, a 5 membered heteroaryl group containing 1 to 3 heteroatoms    selected from oxygen, sulphur and nitrogen and optionally    substituted by C₁₋₄ alkyl S(O)₂C₁₋₄ alkyl or C(O)C₁₋₄ alkyl or R₈    represents a 6 membered heteroaryl group containing 1 to 3 nitrogen    atoms and optionally substituted by C₁₋₄ alkyl, S(O)₂C₁₋₄ alkyl or    C(O)C₁₋₄ alkyl; or R₈ is a C₁₋₆ alkyl group optionally substituted    by one or two groups selected from fluorine, phenyl(optionally    substituted by C₁₋₄ alkyl, C(O)C₁₋₄ alkyl or halogen), ═O, C₃₋₇    cycloalkyl, hydroxy, amino, dimethylamino, aminocarbonyl, C₁₋₄    alkoxy or trifluoromethyl;-   R₉ is hydrogen, C₁₋₄ alkyl or R₉ and R₈ together with nitrogen to    which they are attached are a 5 to 7 membered heterocyclic group    optionally containing another heroatom selected from oxygen, sulphur    and nitrogen and optionally substituted by one or two groups    selected from C₁₋₄ alkyl, ═O, S(O)₂C₁₋₄ alkyl, C(O)C₃₋₇ cycloalkyl    or C(O)C₁₋₄ alkyl;-   R₁₀ and R₁₁ are independently hydrogen or C₁₋₄ alkyl group;-   X represents a nitrogen atom and Y is CH or X represents CH and Y is    nitrogen;-   m is zero or an integer from 1 to 3;-   n is an integer from 1 to 3;-   p is zero, 1 or 2;    and pharmaceutically acceptable salts and solvates thereof.

Suitable pharmaceutically acceptable salts of the compounds of generalformula (I) include acid addition salts formed with pharmaceuticallyacceptable organic or inorganic acids, for example hydrochlorides,hydrobromides, sulphates, alkyl- or arylsulphonates (e.g.methanesulphonates or p-toluenesulphonates), phosphates, acetates,citrates, succinates, tartrates, trifluoroacetates, lactates, fumarates,malates and maleates.

The solvates may, for example, be hydrates.

References hereinafter to a compound according to the invention includeboth compounds of formula (I) and their pharmaceutically acceptable acidaddition salts together with pharmaceutically acceptable solvates.

Suitable pharmaceutical acceptable salts of the compounds of generalformula (I) may be obtained in a crystalline form and/or in an amorphousform or as a mixture thereof.

It will be appreciated by those skilled in the art that the compounds offormula (I) contain at least two chiral centres (namely the carbon atomshown as * in the formulae from 1a to 4h).

Thus, when X is CH, Y is nitrogen, R₅ is hydrogen and R₆ is NR₇R₈, thechiral centres may be represented by the formulae (1a, 1b, 1c e 1d).

When Y is CH and X is nitrogen, R₆ is hydrogen and R₅ is NR₇R₈, thechiral centres may be represented by the formulae (2a, 2b, 2c and 2d).

When Y is CH and X is nitrogen and R₅ is hydrogen and R₆ is NR₇R₈ thechiral centres may be represented by the formulae (3a, 3b, 3c and 3d).

When Y is nitrogen and X is CH and R₅ is NR₇R₈ and R₆ is hydrogen thechiral centres may be represented by the formulae (4a, 4b, 4c and 4d).

The wedge shaped bond indicates that the bond is above the plane of thepaper and it corresponds to the β configuration. The broken bondindicates that the bond is below the plane of the paper and itcorresponds to the α configuration.

In the specific compounds named below when Y is CH and X is nitrogen,the β configuration at the 2 position of the piperidine ring correspondsto the S configuration and the β configuration at the 4 position of thepiperidine ring corresponds to the R configuration. The α configurationat the 2 position of the piperidine ring corresponds to the Rconfiguration and the α configuration at the 4 position of thepiperidine ring corresponds to the S configuration.

In the specific compounds named below when Y is nitrogen and X is CH,the β configuration at the 2 position of the piperidine ring correspondsto the R configuration and the β configuration at the 4 position of thepiperidine ring corresponds to the S configuration. The α configurationat the 2 position of the piperidine ring corresponds to the Sconfiguration and the α configuration at the 4 position of thepiperidine ring corresponds to the R configuration.

The configuration of the chiral carbon atoms of the piperidine ringshown in 1a, 1c, 2b, 2c, 3b, 3c, 4b and 4c, is hereinafter referred toas anti configuration and in formulae 1b, 1d, 2a, 2d, 3a, 3d, 4a and 4das the syn configuration.

The assignment of the R or S configuration at the 2 and the 4 positionshas been made according to the rules of Cahn, Ingold and Prelog,Experientia 1956, 12, 81.

Further asymmetric carbon atoms are possible in the compounds of formula(I). Thus, when R₂ and R₃ are not the same group, the compounds offormula (I) possess at least 3 asymmetric carbon atoms.

It is to be understood that all stereoisomeric forms, including allenantiomers, diastereoisomers and all mixtures thereof, includingracemates, are encompassed within the scope of the present invention andthe reference to compounds of formula (I) includes all stereoisomericforms unless otherwise stated.

Furthermore, some of the crystalline forms of the compounds of structure(I) may exist as polymorphs, which are included in the presentinvention.

The term C₁₋₄ alkyl as used herein as a group or a part of the grouprefers to a straight or branched alkyl group containing from 1 to 4carbon atoms; examples of such groups include methyl, ethyl, propyl,isopropyl, n-butyl, isobutyl, tert-butyl, dimethylpropyl, 1-methylethylor 2-methyl propyl.

The term C₁₋₆ alkyl is meant to include C₁₋₄ alkyl and the higherhomologues thereof having 5 or 6 carbon atoms such as for examplepentyl, 2-methylbutyl, hexyl, 2-methylpentyl or dimethylpropyl.

The term C₃₋₆ alkenyl group refers to a straight or branched alkenylgroup containing from 3 to 6 carbon atoms; examples of such groupsinclude 2-propenyl, 1-propenyl, isopropenyl, 2-butenyl, 2-pentenyl,2-hexenyl and the like.

When R₁ and R₃ together with nitrogen and carbon atom to which they areattached respectively represent a 5 to 6 membered heterocyclic group,this group is saturated or contains a single double bond. This may be a3,6-dihydro-2H-pyridin-1-yl, a piperidin-1-yl or a pyrrolidin-1-ylgroup.

When R₅ is a 5 or 6 membered heteroaryl group according to the inventionit includes furanyl, thiophenyl, imidazolyl, thiazolyl, oxazolyl,pyridyl or pyrimidinyl.

When R₇ and R₈ together with nitrogen to which they are attachedrepresent a 5 to 7 membered heterocyclic group containing oxygen thisgroup may be a morpholinyl (e.g. morpholino), homomorpholinyl,1,3-oxazolidinyl.

When R₉ and R₈ together with nitrogen to which they are attached is a 5to 7 membered heterocyclic group optionally containing anotherheteroatom selected from oxygen, sulphur and nitrogen, this groupincludes piperidinyl, piperazinyl, morpholinyl, pyrazolidinyl,imidazolidinyl or pyrrolidinyl and the like.

When R₈ is saturated 5 to 7 membered heterocyclic group according to theinvention it includes piperidinyl, piperazinyl, morpholinyl,pyrazolidinyl, imidazolidinyl or pyrrolidinyl, 1,3 dioxolan-yl and thelike.

The term C₃₋₇ cycloalkyl group means a non aromatic monocyclichydrocarbon ring of 3 to 7 carbon atoms such as, for example,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl.

The term halogen refers to a fluorine, chlorine, bromine or iodine atom.

The term C₁₋₄ alkoxy group may be a straight chain or a branched chainalkoxy group, for example methoxy, ethoxy, propoxy, prop-2-oxy, butoxy,but-2-oxy or methylprop-2-oxy.

A group of preferred compounds of the invention is that in which R₆ isNR₇R₈ and R₅ is hydrogen, Y is nitrogen and X is CH or wherein R₆ ishydrogen and R₅ is NR₈R₉, Y is CH and X is nitrogen. These compounds arerepresented by the formulae (1) and (2) respectively, wherein R, R₁, R₂,R₃, R₄, R₅, R₆, m and n have the meanings defined for compounds offormula (I).

When Y is nitrogen and X is CH, a preferred group of compounds offormula (I) is that in which the carbon atom at the 2-position of thepiperidine ring is in the β configuration.

A preferred group of compounds of formula (I) is that in which thesubstituents of the piperidine ring are in the syn configuration.

R is preferably a halogen (e.g. fluorine) and/or a C₁₋₄ alkyl (e.g.methyl) group and m is preferably zero or an integer from 1 to 2.

R₁ is preferably a methyl group.

R₂ is preferably a hydrogen atom or a methyl group.

R₃ is preferably a hydrogen atom or a methyl group.

R₄ is preferably a trifluoromethyl group and/or halogen (i.e. chlorine)and n is preferably 2.

R₅ is preferably hydrogen, NH(C₃₋₇ cycloalkyl), NH(C₁₋₄alkyl C₃₋₇cycloalkyl), 1-piperazinyl(optionally substituted by one or two groupsselected from C₁₋₄ alkyl, ═O, S(O)₂C₁₋₄ alkyl, C(O)C₃₋₇ cycloalkyl orC(O)C₁₋₄ alkyl); piperidyl (optionally substituted by one or two groupsselected from C₁₋₄ alkyl, ═O,) or morpholino.

R₆ is preferably hydrogen, N(C₁₋₆alkyl)₂, NH(C₁₋₆alkyl),NH(CH₂)pC(O)NR₁₀R₁₁ wherein p is 1 or 2 and R₉ and R₁₀ are independentlyhydrogen or methyl, NH(C₁₋₆ alkyltrifluoromethyl),NH(C₁₋₆alkylC₁₋₄alkoxy), NH(C₁₋₆alkylfluorine), N(C₁₋₆ alkyl)(C₁₋₆alkylfluorine), NH(C₁₋₆ alkylphenyl), NH(C₃₋₇cycloalkyl), NH(piperidyl),NH(C₁₋₆ alkyl aminocarbonyl), NH(C₁₋₆ alkyl-1,3 dioxolan-yl) ormorpholino.

R₇ is preferably a hydrogen atom or a methyl group.

R₈ is preferably hydrogen, C₁₋₆ alkyl, C₃₋₇ cycloalkyl, CH2C(O)NH₂, C₁₋₆alkyl trifluoromethyl, C₁₋₆ alkylC₁₋₄ alkoxy, C₁₋₆ alkylfluorine, C₁₋₆alkylphenyl, piperidyl, C₁₋₆ alkyl aminocarbonyl, C₁₋₆ alkyl 1,3dioxolanyl.

R₉ is preferably a hydrogen atom or a methyl group.

R₁₀ is preferably a hydrogen atom or a methyl group.

R₁₁ is preferably a hydrogen atom or a methyl group.

A preferred class of compounds of formula (I) is that wherein each R isindependently a halogen (e.g. fluorine) or a C₁₋₄ alkyl (e.g. methyl)group, wherein m is 0, 1 or 2. More preferably m is 1 or 2. Within thisclass, those wherein R is at the 2 and/or 4 position in the phenyl ringare particularly preferred.

Compounds of formula (I), wherein n is 2, represent a preferred class ofcompounds and within this class the groups R₄ are preferably at the 3and 5 position in the phenyl ring.

Further preferred compounds of formula (I) are those wherein

-   R₆ is NR₇R₈ and R₅ is hydrogen, Y is nitrogen and X is CH or wherein    R₆ is hydrogen and R₅ is NR₈R₉, Y is CH and X is nitrogen;-   R₇ is hydrogen or methyl;-   R₈ is methyl, ethyl, dimethylpropyl, cyclopropyl, cyclobutyl,    CH₂C(O)NH₂, piperidinyl, 1-methyl-piperidinyl, methyl substituted by    a group selected from phenyl, cyclopropyl, 4-acetyl-piperazino,    fluorine, methoxy, trifluoromethyl and 1,3 dioxolanyl;-   R₉ is hydrogen or methyl;-   R₉ and R₈ together with nitrogen to which they are attached is    1-piperazinyl, acetyl-1-piperazinyl, morpholino;-   R₇ and R₈ together with nitrogen to which they are attached is    morpholino;-   R is independently fluorine or methyl;-   R₄ is trifluoromethyl and/or chlorine;-   m is 1 or 2;-   n is 2.

Preferred compounds according to the invention are:

-   4-(2,2-Dimethyl-propylamino)-2-(4-fluoro-2-methyl-phenyl)-piperidine-1-carboxylic    acid, [1-(R)-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-methylamide;-   Ethylamino-2-(4-fluoro-2-methyl-phenyl)-piperidine-1-carboxylic acid    [1-(R)-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-methylamide;-   4-Dimethylamino-2-(4-fluoro-2-methyl-phenyl)-piperidine-1-carboxylic    acid [1-(R)-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-methylamide;-   4-Dimethylamino-2-(R)-(4-fluoro-2-methyl-phenyl)-piperidine-1-carboxylic    acid (3,5-bis-trifluoromethyl-benzyl)-methylamide;-   4-(2-Fluoroethyl)-amino-2-(4-fluoro-2-methyl-phenyl)-piperidine-1-carboxylic    acid [1-(R)-(3,5-bis)-trifluoromethyl-phenyl)-ethyl]-methylamide;-   4-(2-Fluoro-ethylamino)-2-(4-fluoro-2-methyl-phenyl)-piperidine-1-carboxylic    acid (3,5-bis-trifluoromethyl-benzyl)-methylamide;-   4-(N-2-Fluoroethyl-N-methylamino)-2-(4-fluoro-2-methyl-phenyl)-piperidine-1-carboxylic    acid, (3,5-bis-trifluoromethyl-benzyl)-methylamide;-   2-(4-Fluoro-2-methyl-phenyl)-4-(2-methoxyethylamino)-piperidine-1-carboxylic    acid [1-(R)-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-methylamide;-   2-(4-Fluoro-2-methyl-phenyl)-4-methylamino-piperidine-1-carboxylic    acid [1-(R)-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-methylamide;-   2-(4-Fluoro-2-methyl-phenyl)-4-methylamino-piperidine-1-carboxylic    acid (3,5-bis-trifluoromethyl-benzyl)-methylamide;-   2-(4-Fluoro-2-methyl-phenyl)-4-methylamino-piperidine-1-carboxylic    acid (3,5-bis-trifluoromethyl-benzyl)-methylamide;-   4-Amino-2-(4-fluoro-2-methyl-phenyl)-piperidine-1-carboxylic acid    (3,5-bis-trifluoromethyl-benzyl)-methylamide;-   4-Cyclobutylamino-2-(4-fluoro-2-methyl-phenyl)-piperidine-1-carboxylic    acid [1-(R)-(3,5-bis)-trifluoromethyl-phenyl)-ethyl]-methylamide;-   4-Cyclopropylamino-2-(4-fluoro-2-methyl-phenyl)-piperidine-1-carboxylic    acid [1-(R)-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-methylamide;-   2-(4-Fluoro-2-methyl-phenyl)-4-[methyl-(1-methyl-piperidin-4-yl)amino]-piperidine-1-carboxylic    acid [1-(R)-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-methyl-amide;-   4-Benzylamino-2-(4-fluoro-2-methyl-phenyl)-piperidine-1-carboxylic    acid (3,5-bis-trifluoromethyl-benzyl)-methylamide;-   4-[(1,3-Dioxolan-2-yl)-methyl]-amino-2-(4-fluoro-2-methyl-phenyl)-piperidine-1-carboxylic    acid, (3,5-bis-trifluoromethyl-benzyl)-methylamide;-   4-(-N-2-Fluoroethyl-N-methylamino)-2-(R)-(4-fluoro-2-methyl-phenyl)-piperidine-1-carboxylic    acid (3,5-bis-trifluoromethyl-benzyl)-methylamide;-   4-(Carbamoylmethyl-amino)-2-(4-fluoro-2-methyl-phenyl)-piperidine-1-carboxylic    acid (3,5-bis-trifluoromethyl-benzyl)-methylamide;-   2-(4-Fluoro-2-methyl-phenyl)-4-morpholino-piperidine-1-carboxylic    acid (3,5-bis-trifluoromethyl-benzyl)-methylamide;-   2-(4-Fluoro-2-methyl-phenyl)-4-morpholino-piperidine-1-carboxylic    acid 1-[(R)-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-methylamide;-   2-(4-Fluoro-2-methyl-phenyl)-4-morpholino-piperidine-1-carboxylic    acid 1-[(S)-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-methylamide;-   4-Cyclopropylamino-1-(4-fluoro-2-methyl-phenyl)-piperidine-2-carboxylic    acid (3,5-dichloro-benzyl)-methylamide;-   4-(4-Acetyl-piperazin-1-yl)-1-(4-fluoro-2-methyl-phenyl)-piperidine-2-carboxylic    acid (3,5-dichloro-benzyl)-methylamide;-   4-Cyclopropylamino-1-(4-fluoro-2-methyl-phenyl)-piperidine-2-carboxylic    acid [1-(R)-3,5-bis-trifluoromethyl-phenyl)-ethyl]-methylamide;-   4-Cyclopropylmethylamino-1-(4-fluoro-2-methyl-phenyl)-piperidine-2-carboxylic    acid (3,5-ditrifluoromethyl-benzyl)-methylamide;-   1-(4-Fluoro-2-methyl-phenyl)-4-morpholino-piperidine-2-carboxylic    acid (3,5-bis-trifluoromethyl-benzyl)-methylamide;-   4-(4-Acetylpiperazinyl)-1-(4-fluoro-2-methyl-phenyl)-piperidine-2-carboxylic    acid, (3,5-bis-trifluoromethyl-benzyl)-methylamide;    diastereoisomers and acceptable pharmaceutical salts thereof.

Particularly preferred compounds of the invention are:

-   4-(S)-Dimethylamino-2-(R)-(4-fluoro-2-methyl-phenyl)-piperidine-1-carboxylic    acid [1-(R)-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-methylamide    hydrochloride;-   4-(S)-Dimethylamino-2-(R)-(4-fluoro-2-methyl-phenyl)-piperidine-1-carboxylic    acid (3,5-bis-trifluoromethyl-benzyl)-methylamide hydrochloride;-   4-(S)-(2-Fluoroethyl)-amino-2-(R)-(4-fluoro-2-methyl-phenyl)-piperidine-1-carboxylic    acid [1-(R)-(3,5-bis)-trifluoromethyl-phenyl)-ethyl]-methylamide    hydrochloride;-   4-(S)-(2-Fluoro-ethylamino)-2-(R)-(4-fluoro-2-methyl-phenyl)-piperidine-1-carboxylic    acid (3,5-bis-trifluoromethyl-benzyl)-methylamide hydrochloride.    4-(S)-Dimethylamino-2-(R)-(4-fluoro-2-methyl-phenyl)-piperidine-1-carboxylic    acid [1-(R)-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-methylamide    hydrochloride;-   4-(S)-Dimethylamino-2-(R)-(4-fluoro-2-methyl-phenyl)-piperidine-1-carboxylic    acid (3,5-bis-trifluoromethyl-benzyl)-methylamide hydrochloride;-   4-(S)-(2-Fluoroethyl)amino-2-(R)-(4-fluoro-2-methyl-phenyl)-piperidine-1-carboxylic    acid [1-(R)-(3,5-bis)-trifluoromethyl-phenyl)-ethyl]-methylamide    hydrochloride;-   4-(S)-(2-Fluoro-ethylamino)-2-(R)-(4-fluoro-2-methyl-phenyl)-piperidine-1-carboxylic    acid (3,5-bis-trifluoromethyl-benzyl)-methylamide hydrochloride.

The compounds of the invention are antagonists of tachykinins, includingsubstance P and other neurokinins, both in vitro and in vivo and arethus of use in the treatment of conditions mediated by tachykinins,including substance P and other neurokinins.

The compounds of the present invention have also activity as serotoninre-uptake inhibitors.

Tachykinins are a family of peptides that share a commoncarboxyl-terminal sequence (Phe-X-Gly-Leu-Met-NH2). They are activelyinvolved in the physiology of both lower and advanced lifeforms. Inmammalian lifeforms, the main tachykinins are substance P (SP),Neurokinin A (NKA) and Neurokinin B (NKB) which act as neurotransmittersand neuromodulators. Mammalian tachykinins may contribute to thepathophysiology of a number of human diseases.

Three types of tachykinins receptors have been identified, namelyNK1(SP-preferring), NK2 (NKA-preferring) and NK3 (NKB-preferring) whichare widely distributed throughout the central nervous (CNS) andperipheral nervous system.

Particularly, the compounds of the invention are antagonists of the NK1receptor.

By virtue of their efficacy as tachykinins receptor (expecially NK1receptor) antagonists, the compounds of the present invention areparticularly useful for the treatment of CNS disorders and psychoticdisorders, in particular in the treatment or prevention of depressivestates and/or in the treatment of anxiety.

NK₁-receptor binding affinity has been determined in vitro by measuringthe compounds' ability to displace [3H]-substance P (SP) fromrecombinant human NK₁ receptor expressed in Chinese Hamster Ovary (CHO)cell membranes and from gerbil and marmoset brain cortex homogenates.

Membrane preparation from hNK1-CHO cells were performed essentially asdescribed by Beattie et al. (Br. J. Pharmacol, 116:3149-3157, 1995).

hNK1-CHO cells were harvested in phosphate buffered saline (PBS)containing 5 mM EDTA and centrifuged at 913 g for 8 min at 4° C. Cellswere then re-suspended in 10 volumes of membrane-preparation buffer(HEPES 50 mM, pH 7.4, containing 0.1 mM leupeptin, 40 μg/ml bacitracin,1 mM EDTA, 1 mM Pefabloc and 2 μM pepstatin A) and homogenised. Thesuspension was centrifuged at 48,000 g for 20 minutes at 4° C. The finalpellet was re-suspended in 10 volumes of membrane preparation buffer andre-homogenised. Suspensions of membrane were then frozen at −80° C.until required.

The assay volume of 200 μl consisted of 2 μl of DMSO or increasingconcentrations of test compound dissolved in DMSO (1 pM-1 μM finalconcentration), 100 μl of [3H]—SP (0.5 nM final concentration), and 100μl of membrane suspension (8 μg of protein per well) in incubationbuffer (containing 50 mM HEPES, pH 7.4, 3 mM MnCl2, and 0.02% BSA). Theincubation was carried out at room temperature for 40 min. Non-specificbinding was defined by the addition of cold SP (1 μM). The reaction wasstopped by rapid filtration. Filters were washed 5 times with 200 μl ofice-cold 0.9% w/v NaCl, and radioactivity was counted in a microplatescintillation counter. In each experiment, every concentration ofdisplacer was tested in duplicate.

Mongolian gerbil (60 g, Charles River) and common marmoset (Callithrixjacchus, 300-400 g, GSK colony, Verona, Italy) brain cortex homogenateswere prepared as follows: fresh tissues were weighed, crumbled andhomogenised in 10 volumes of membrane-preparation buffer. The homogenatewas then centrifuged at 48,000 g for 20 minutes, and the pellet waswashed once more by resuspension in 10 volumes of membrane preparationbuffer and centrifugation at 48,000 g for 20 minutes. The final pelletwas re-suspended in 7-10 volumes of membrane preparation buffer andsubdivided in aliquots frozen at −80° C. until use.

The assay volume of 400 μl consisted of 100 μl of incubation buffer(containing 50 mM HEPES, pH 7.4, 3 mM MnCl2, and 0.02% BSA), 4 μl ofDMSO or increasing concentrations of test compound dissolved in DMSO (1pM-1 μM final concentration), 100 μl of [3H]—SP (0.5 nM-0.8 nM finalconcentration) in incubation buffer and 200 μl of membrane suspension(0.6 mg protein for gerbil, and 0.8 mg protein for marmoset) inincubation buffer containing 2 μg/ml leupeptin, 20 μg/ml bacitracin and0.5 μM phosphoramidon. The incubation proceeded at room temperature for60 min. Non-specific binding was defined by the addition of cold SP (1μM). The reaction was stopped by rapid filtration. Filters were washed 3times with 1 ml ice cold wash buffer (containing 50 mM HEPES, pH 7.4,and 3 mM MnCl2), and radioactivity was counted in a liquid scintillationcounter.

The potency of test compounds to inhibit SP or GR₇₃₆₃₂-induced increaseof [Ca2+]i in hNK1/CHO cells was determined in functional experiments byusing FLIPR (fluorimetric imaging plate reader) technology. hNK1/CHOcells were seeded at a density of 60,000 cells per well and culturedovernight in Ham's F-12 medium supplemented with 10% (v/v)heat-inactivated foetal bovine serum and 2 mM glutamine. The cells werethen incubated for the labelling in the culture medium containing thefluorescent calcium indicator Fluo-4 AM (2 μM), the organic anionstransport blocker probenecid (5 mM), and HEPES (20 mM) for 30 min in ahumidified atmosphere of 5% CO2. After washing with Hanks' BalancedSalts Solution (HBSS) containing 20 mM HEPES and 2.5 mM probenecid, thecells were incubated for 60 min at 37 C in wash buffer containing 0.02%BSA either in the absence (control) or in the presence of testcompounds. The plates were then placed into a FLIPR to monitor cellfluorescence (ex488 nm, em=510-570 nm) before and after the addition ofdifferent concentrations of SP or GR₇₃₆₃₂ in assay buffer. Experimentswere carried out by using a laser setting of 1.0 W and a 0.4 sec chargecoupled device (CCD) camera shutter speed.

Compounds of the invention have also been found to exhibit anxiolyticactivity in conventional tests. For example in marmoset human threattest (Costall et al., 1988).

Human Serotonin Transporter (hSERT) binding affinity has been determinedin vitro by the compounds' ability to displace [³C]—Imipramine fromhuman serotonin transporter expressed in Human Embryonic Kidney HEK293cell membranes (Receptor Biology Inc.). For the binding reaction, 4 nMof [³H]—Imipramine (703 GBq/mmol, Amersham) were incubated with 0.02mg/ml of cell membrane and the compound to be tested at differentconcentrations (7 concentration points) in 50 mM Tris HCl, pH 7.5, 120mM of NaCl and 5 mM KCl. The reaction was performed for 60 min at 4° C.and was terminated by filtration through GF/B Unifilters 96 wells/case(presoaked in 0.5% PEI) using a Cell Harvester (Packard). Scintillationfluid was added to each filtered spot and radioactivity was determinedusing a scintillation counter (TopCount (Packard)). Non-specific bindingwas determined using Imipramine (100 μM) and represents about 5% of thetotal binding.

Competition experiments were conducted with duplicate determination foreach point. Msat601 software package was used to elaborate thecompetition binding data. IC₅₀ values were converted to K_(i) valuesusing Cheng-Prusoff equation.

The inhibitory activity of the compounds at the rat serotonintransporter has been determined in vitro using rSERT-LLCPK cells (LLCPKcells tranfected with the rat SERT). The cells have been plated onto96-well plates (60000 cells/well). After 24 hr, cells have been washedin uptake buffer (Hank's balanced salt solution+20 mM Hepes) andpre-incubated for 10 min at RT with 50 μl of buffer containing the testcompounds. 50 μl of 50 nM [3H] Serotonin (5HT) solution (finalconcentration: 25 nM [3H] 5HT) have been added and plates have beenincubated for 7 min at RT, during which cells take up radiolabelled 5HT.Aspirating the solution and rapidly washing the cells with cold bufferhas terminated the uptake.

The amount of radioactive 5HT incorporated in the cells has been thenmeasured by adding the scintillation cocktail directly onto the cellsand reading the plate in the Top Count. The data have been digitallyprocessed to obtain the pIC50 values of the antagonists. The pKi valueshave been calculated using the Chen-Prusoff equation.

The action of the compounds of the invention at the NK₁ receptor may bedetermined by using conventional tests. Thus, the ability to penetratethe central nervous system and to bind at the NK₁ receptor wasdemonstrated in vivo by their inhibitory effect on the change in thebehaviour induced by intracerebroventricular applied substance P in thegerbil, according to the gerbil foot tapping model as described byRupniak & Williams, Eur. J. of Pharmacol., 265, 179-183, 1994.

Compounds of the invention are useful in the treatment of CNS disordersand psychotic disorders, in particular in the treatment or prevention ofdepressive states and/or in the treatment of anxiety as defined in, butnot restricted to, Diagnostic Statistical of Mental Disorder (DSM) IVedition edit by American Psychiatric Association and InternationalClassification Diseases 10th revision (ICD10).

Thus, for example, depressive states include Major Depressive Disorders(MDD), including bipolar depression, unipolar depression, single orrecurrent major depressive episodes, recurrent brief depression, with orwithout psychotic features, catatonic features, melancholic featuresincluding anorexia, weight loss, atypical features, anxious depression,cyclothymic or postpartum onset.

Other mood disorders encompassed within the term major depressivedisorders include dysthymic disorders with early or late onset and withor without atypical features, neurotic depression, post-traumatic stressdisorders and social phobia; dementia of the Alzheimer's type, withearly or late onset, with depressed mood; vascular dementia withdepressed mood; mood disorders induced by alcohol, amphetamines,cocaine, hallucinogens, inhalants, opioids, phencyclidine, sedatives,hypnotics, anxiolytics and other substances; schizoaffective disorder ofthe depressed type; and adjustment disorder with depressed mood. Majordepressive disorders may also result from a general medical conditionincluding, but not limited to, myocardial infarction, diabetes,miscarriage or abortion, etc.

The term anxiety includes anxiety disorders, such as panic disorderswith or without agoraphobia, agoraphobia, phobias, for example, socialphobias or agoraphobia, obsessive-compulsive disorder, stress disordersincluding post-traumatic stress disorders, generalised anxietydisorders, acute stress disorders and mixed anxiety-depressiondisorders.

Compounds of the invention are useful as analgesics. In particular, theyare useful in the treatment of traumatic pain such as postoperativepain; traumatic avulsion pain such as brachial plexus; chronic pain suchas arthritic pain such as occurring in osteo-, rheumatoid or psoriaticarthritis; neuropathic pain such as post-herpetic neuralgia, trigeminalneuralgia, segmental or intercostal neuralgia, fibromyalgia, causalgia,peripheral neuropathy, diabetic neuropathy, chemotherapy-inducedneuropathy, AIDS related neuropathy, occipital neuralgia, geniculateneuralgia, glossopharyngeal neuralgia, reflex sympathetic dystrophy,phantom limb pain; various forms of headache such as migraine, acute orchronic tension headache, temporomandibular pain, maxillary sinus pain,cluster headache; odontalgia; cancer pain; pain of visceral origin;gastrointestinal pain; nerve entrapment pain; sport's injury pain;dysmennorrhoea; menstrual pain; meningitis; arachnoiditis;musculoskeletal pain; low back pain e.g. spinal stenosis; prolapseddisc; sciatica; angina; ankylosing spondyolitis; gout; bums; scar pain;itch and thalamic pain such as post stroke thalamic pain.

Compounds of the invention are also useful in the treatment of sleepdisorders including dysomnia, insomnia, sleep apnea, narcolepsy, andcircadian ritmic disorders.

Compounds of the invention are also useful in the treatment orprevention of the cognitive disorders. Cognitive disorders includedementia, amnestic disorders and cognitive disorders not otherwisespecified.

Furthermore, compounds of the invention are also useful as memory and/orcognition enhancers in healthy humans with no cognitive and/or memorydeficit.

Compounds of the invention are also useful in the treatment of toleranceto and dependence on a number of substances. For example, they areuseful in the treatment of dependence on nicotine, alcohol, caffeine,phencyclidine (phencyclidine like compounds) or in the treatment oftolerance to and dependence on opiates (e.g. cannabis, heroin, morphine)or benzodiazepines; in the treatment of addiction to cocaine, sedativeipnotic, amphetamine or amphetamine-related drugs (e.g.dextroamphetamine, methylamphetamine) or a combination thereof.

Compounds of the invention are also useful as anti-inflammatory agents.In particular, they are useful in the treatment of inflammation inasthma, influenza, chronic bronchitis and rheumatoid arthritis; in thetreatment of inflammatory diseases of the gastrointestinal tract such asCrohn's disease, ulcerative colitis, inflammatory bowel disease andnon-steroidal anti-inflammatory drug induced damage; inflammatorydiseases of the skin such as herpes and eczema; inflammatory diseases ofthe bladder such as cystitis and urge incontinence; and eye and dentalinflammation.

Compounds of the invention are also useful in the treatment of allergicdisorders, in particular allergic disorders of the skin such asurticaria, and allergic disorders of the airways such as rhinitis.

Compounds of the invention are also useful in the treatment orprevention of schizophrenic disorders including paranoid schizophrenia,disorganised schizophrenia, catatonic schizophrenia, undifferentiatedschizophrenia, residual schizophrenia.

Compounds of the invention are also useful in the treatment of emesis,i.e. nausea, retching and vomiting. Emesis includes acute emesis,delayed emesis and anticipatory emesis. The compounds of the inventionare useful in the treatment of emesis however induced. For example,emesis may be induced by drugs such as cancer chemotherapeutic agentssuch as alkylating agents, e.g. cyclophosphamide, carmustine, lomustineand chlorambucil; cytotoxic antibiotics, e.g. dactinomycin, doxorubicin,mitomycin-C and bleomycin; anti-metabolites, e.g. cytarabine,methotrexate and 5-fluorouracil; vinca alkaloids, e.g. etoposide,vinblastine and vincristine; and others such as cisplatin, dacarbazine,procarbazine and hydroxyurea; and combinations thereof; radiationsickness; radiation therapy, e.g. irradiation of the thorax or abdomen,such as in the treatment of cancer; poisons; toxins such as toxinscaused by metabolic disorders or by infection, e.g. gastritis, orreleased during bacterial or viral gastrointestinal infection;pregnancy; vestibular disorders, such as motion sickness, vertigo,dizziness and Meniere's disease; post-operative sickness;gastrointestinal obstruction; reduced gastrointestinal motility;visceral pain, e.g. myocardial infarction or peritonitis; migraine;increased intercranial pressure; decreased intercranial pressure (e.g.altitude sickness); opioid analgesics, such as morphine; andgastro-oesophageal reflux disease (GERD) such as erosive GERD andsymptomatic GERD or non erosive GERD, acid indigestion, over-indulgenceof food or drink, acid stomach, sour stomach, waterbrash/regurgitation,heartburn, such as episodic heartburn, nocturnal heartburn, andmeal-induced heartburn, dyspepsia and functional dyspepsia.

Compounds of the invention are also useful in the treatment ofgastrointestinal disorders such as irritable bowel syndrome,gastro-oesophageal reflux disease (GERD) such as erosive GERD andsymptomatic GERD or non erosive GERD, acid indigestion, over-indulgenceof food or drink, acid stomach, sour stomach, waterbrash/regurgitation,heartburn, such as episodic heartburn, nocturnal heartburn, andmeal-induced heartburn, dyspepsia and functional dyspepsia (such asulcer-like dyspepsia, dysmotility-like dyspepsia and unspecifieddyspepsia) chronic constipation; skin disorders such as psoriasis,pruritis and sunburn; vasospastic diseases such as angina, vascularheadache and Reynaud's disease; cerebral ischeamia such as cerebralvasospasm following subarachnoid haemorrhage; fibrosing and collagendiseases such as scleroderma and eosinophilic fascioliasis; disordersrelated to immune enhancement or suppression such as systemic lupuserythematosus and rheumatic diseases such as fibrositis; and cough.

The compounds of the invention are also useful in premenstrual dysphoricdisorder (PMDD), in chronic fatigue syndrome and Multiple sclerosis.

Compounds of the invention have been found to exhibit anxiolytic andantidepressant activity in conventional tests. For example, in Guineapig pups separation-induced vocalisations (Molewijk et al., 1996).

Compounds of the invention are also useful in the treatment ofconvulsions and epilepsy.

Compounds of the invention may be administered in combination with otheractive substances such as 5HT3 antagonists, serotonin agonists,selective serotonin reuptake inhibitors (SSRI), noradrenaline re-uptakeinhibitors (SNRI), tricyclic antidepressants or dopaminergicantidepressants.

Suitable 5HT3 antagonists which may be used in combination with thecompounds of the inventions include for example ondansetron, granisetronand metoclopramide.

Suitable serotonin agonists which may be used in combination with thecompounds of the invention include sumatriptan, rauwolscine, yohimbineand metoclopramide.

Suitable SSRI which may be used in combination with the compounds of theinvention include fluoxetine, citalopram, femoxetine, fluvoxamine,paroxetine, indalpine, sertraline and zimeldine.

Suitable SNRI which may be used in combination with the compounds of theinvention include venlafaxine and reboxetine.

Suitable tricyclic antidepressants which may be used in combination witha compound of the invention include imipramine, amitriptiline,chlomipramine and nortriptiline.

Suitable dopaminergic antidepressants which may be used in combinationwith a compound of the invention include bupropion and amineptine.

It will be appreciated that the compounds of the combination may beadministered simultaneously (either in the same or differentpharmaceutical formulations) or sequentially.

The invention therefore provides a compound of formula (I) or apharmaceutically acceptable salt or solvate thereof for use in therapy,in particular in human medicine.

There is also provided as a further aspect of the invention the use of acompound of formula (I) or a pharmaceutically acceptable salt or solvatethereof in the preparation of a medicament for use in the treatment ofconditions mediated by tachykinins, including substance P and otherneurokinins.

In an alternative or further aspect there is provided a method for thetreatment of a mammal, including man, in particular in the treatment ofconditions mediated by tachykinins, including substance P and otherneurokinins, comprising administration of an effective amount of acompound of formula (I) or a pharmaceutically acceptable salt thereof.

It will be appreciated that reference to treatment is intended toinclude prophylaxis as well as the alleviation of established symptoms.Compounds of formula (I) may be administered as the raw chemical but theactive ingredient is preferably presented as a pharmaceuticalformulation.

Accordingly, the invention also provides a pharmaceutical compositionwhich comprises at least one compound of formula (I) or apharmaceutically acceptable salt thereof and formulated foradministration by any convenient route. Such compositions are preferablyin a form adapted for use in medicine, in particular human medicine, andcan conveniently be formulated in a conventional manner using one ormore pharmaceutically acceptable carriers or excipients.

Thus, compounds of formula (I) may be formulated for oral, buccal,parenteral, topical (including ophthalmic and nasal), depot or rectaladministration or in a form suitable for administration by inhalation orinsufflation (either through the mouth or nose).

For oral administration, the pharmaceutical compositions may take theform of, for example, tablets or capsules prepared by conventional meanswith pharmaceutically acceptable excipients such as binding agents (e.g.pregelatinised maize starch, polyvinylpyrrolidone or hydroxypropylmethylcellulose); fillers (e.g. lactose, microcrystalline cellulose orcalcium hydrogen phosphate); lubricants (e.g. magnesium stearate, talcor silica); disintegrants (e.g. potato starch or sodium starchglycollate); or wetting agents (e.g. sodium lauryl sulphate). Thetablets may be coated by methods well known in the art. Liquidpreparations for oral administration may take the form of, for example,solutions, syrups or suspensions, or they may be presented as a dryproduct for constitution with water or other suitable vehicle beforeuse. Such liquid preparations may be prepared by conventional means withpharmaceutically acceptable additives such as suspending agents (e.g.sorbitol syrup, cellulose derivatives or hydrogenated edible fats);emulsifying agents (e.g. lecithin or acacia); non-aqueous vehicles (e.g.almond oil, oily esters, ethyl alcohol or fractionated vegetable oils);and preservatives (e.g. methyl or propyl-p-hydroxybenzoates or sorbicacid). The preparations may also contain buffer salts, flavouring,colouring and sweetening agents as appropriate.

Preparations for oral administration may be suitably formulated to givecontrolled release of the active compound.

For buccal administration the composition may take the form of tabletsor lozenges formulated in a conventional manner.

The compounds of the invention may be formulated for parenteraladministration by bolus injection or continuous infusion. Formulationsfor injection may be presented in unit dosage form e.g. in ampoules orin multi-dose containers, with an added preservative. The compositionsmay take such forms as suspensions, solutions or emulsions in oily oraqueous vehicles, and may contain formulatory agents such as suspending,stabilising and/or dispersing agents. Alternatively, the activeingredient may be in powder form for constitution with a suitablevehicle, e.g. sterile pyrogen-free water, before use.

The compounds of the invention may be formulated for topicaladministration in the form of ointments, creams, gels, lotions,pessaries, aerosols or drops (e.g. eye, ear or nose drops). Ointmentsand creams may, for example, be formulated with an aqueous or oily basewith the addition of suitable thickening and/or gelling agents.Ointments for administration to the eye may be manufactured in a sterilemanner using sterilised components.

Lotions may be formulated with an aqueous or oily base and will ingeneral also contain one or more emulsifying agents, stabilising agents,dispersing agents, suspending agents, thickening agents, or colouringagents. Drops may be formulated with an aqueous or non-aqueous base alsocomprising one or more dispersing agents, stabilising agents,solubilising agents or suspending agents. They may also contain apreservative.

The compounds of the invention may also be formulated in rectalcompositions such as suppositories or retention enemas, e.g. containingconventional suppository bases such as cocoa butter or other glycerides.

The compounds of the invention may also be formulated as depotpreparations. Such long acting formulations may be administered byimplantation (for example subcutaneously or intramuscularly) or byintramuscular injection. Thus, for example, the compounds of theinvention may be formulated with suitable polymeric or hydrophobicmaterials (for example as an emulsion in an acceptable oil) or ionexchange resins, or as sparingly soluble derivatives, for example, as asparingly soluble salt.

For intranasal administration, the compounds of the invention may beformulated as solutions for administration via a suitable metered orunitary dose device or alternatively as a powder mix with a suitablecarrier for administration using a suitable delivery device.

A proposed dose of the compounds of the invention is 1 to about 1000 mgper day. It will be appreciated that it may be necessary to make routinevariations to the dosage, depending on the age and condition of thepatient and the precise dosage will be ultimately at the discretion ofthe attendant physician or veterinarian. The dosage will also depend onthe route of administration and the particular compound selected.

Compounds of formula (I), and salts and solvates thereof, may beprepared by the general methods outlined hereinafter. In the followingdescription, the groups R, R₁, R₂, R₃, R₄, R₅ R₆R₇R₈R₉, R₁₀ or R₁₁ m, nand p have the meaning as previously defined for compounds of formula(I) unless otherwise stated.

Compounds of formula (I) may be prepared by reductive N-alkylation of acompound of formula (II), wherein R₁₂ is ═O and R₁₃ is hydrogen or R₁₂is hydrogen and R₁₃ is ═O

with an amine derivative (III) or salts thereof. The reaction isconveniently carried out in an aprotic solvent such as dichloroethaneand in the presence of a suitable metal reducing agent such as sodiumborohydride or sodium triacetoxyborohydride.

In a further embodiment of the invention, compounds of formula (I),wherein X is CH, Y is nitrogen may be prepared by reaction of a compoundof formula (IV)

with triphosgene in an aprotic solvent such as dichloromethane and inthe presence of an organic base such triethylamine to form theintermediate compound (V) which may be isolated if required, followed byreaction of compound (V) with the amine compound (VI).

The reaction conveniently takes place in an aprotic solvent such as ahydrocarbon, a halohydrocarbon such as dichloromethane or an ether suchas tetrahydrofuran optionally in the presence of a base such as atertiary amine e.g. diisopropylethylamine.

In a further embodiment of the invention, compounds of formula (I)wherein X is nitrogen and Y is CH may be prepared by reaction of anactivated derivative of the carboxylic acid of formula (VII), with amine(VI) or salts thereof, optionally in the presence of a suitable base.

Suitable activated derivatives of the carboxyl group include thecorresponding acyl halide, mixed anhydride, activated ester such as athioester or a derivative formed between the carboxylic acid group and acoupling agent such as that used in peptide chemistry, for exampleO-(benzotriazol-1-yl)-N,N,N′N′-tetramethyluronium tetrafluoroborate.

The reaction is preferably carried out in an aprotic solvent such as anether, e.g. tetrahydrofuran, a halohydrocarbon, e.g. dichloromethane,N,N-dimethylformamide or acetonitrile.

Suitable base for use in this reaction includes organic base such astriethylamine or N,N diisopropylethylamine.

The activated derivatives of the carboxylic acid (VI) may be prepared byconventional means. A particularly suitable activated derivative for usein this reaction is obtained by reaction of the carboxylic acid (II)with O-(benzotriazol-1-yl)-N,N,N′N′-tetramethyluronium tetrafluoroboratein a suitable aprotic solvent such as an ether e.g. tetrahydrofuran, ahalohydrocarbon e.g. dichloromethane, an amide e.g.N,N-dimethylformamide or acetonitrile.

Compounds of formula (II), in which X is CH, Y is nitrogen may beprepared by treating compounds of formula (VIII), wherein R₁₂ and R₁₃have the meanings defined for compounds of formula (II) wherein Ra is anitrogen protective group,

using the same procedures described above for the preparation ofcompounds of formula (I) from compounds of formula (IV) after removal ofnitrogen protecting group Ra.

Compounds of formula (II), wherein R₁₂ and R₁₃ have the meanings definedfor compounds of formula (II) and in which Y is nitrogen, X is CH, maybe prepared by treating compounds of formula (IX)

using the same procedures described above for the preparation ofcompounds of formula (II) from compounds of formula (VII).

Compounds of formulae (IV) and (VII) may be prepared by reductiveN-alkylation of a piperidine of formula (VIII) and a carboxylic acid(IX) or esters thereof (such as methyl, ethyl and the like) respectivelywith an amine derivative (III) or salts thereof. The reaction isconveniently carried out in an aprotic solvent such as dichloroethaneand in the presence of a suitable metal reducing agent such as sodiumborohydride or sodium triacetoxyborohydride.

Compounds of formula (VIII) are either known compounds or may beprepared by analogous methods to those used for known compounds.

Thus, for example, compound (VIII) and enantiomers thereof may beprepared using Comins reaction as described in Journal American ChemicalSociety 1994,116, 4719-4728, followed by reduction of 2,3dihydro-1H-pyridin-4-one derivative to piperidine-4-one derivative. Thereduction may be effected using hydrogen and metal catalyst e.g.palladium on a suitable support e.g. carbon or alumina. The reaction iscarried out in a solvent such as ester e.g. ethyl acetate.

Compounds of formula (IX) wherein R₁₃ is ═O and R₉ is hydrogen are knowncompounds and they may be prepared according to the procedures asdescribed in Bioorganic & Medicinal Chemistry Letters, Vol 2, N^(o)11,pp 1357-1360, 1992.

Compounds of formula (IX) wherein R₁₂ is ═O and R₈ is hydrogen are novelcompounds and they may be prepared for example by reaction of an amine(XIV) with ethyl glyoxalate to obtain the intermediates (XIII) which maybe converted into 4-oxo-tetrahydropyridine intermediates (XII) which inturn may be reduced to an intermediate of formula (XI). Saidintermediate (XI) may be in turn hydrolysed, thus forming anintermediate of formula (IX).

Compounds of formula (III) are known compounds or may be prepared byanalogous methods to those used for known compounds.

Where it is desired to isolate a compound of formula (I) as a salt, forexample a pharmaceutically acceptable salt, this may be achieved byreacting the compound of formula (I) in the form of the free base withan appropriate amount of suitable acid and in a suitable solvent such asan alcohol (e.g. ethanol or methanol), an ester (e.g. ethyl acetate) oran ether (e.g. diethyl ether or tetrahydrofuran).

Pharmaceutically acceptable salts may also be prepared from other salts,including other pharmaceutically acceptable salts of the compounds offormula (I) using conventional methods.

The compounds of formula (I) may readily be isolated in association withsolvent molecules by crystallisation from or evaporation of anappropriate solvent to give the corresponding solvates.

When a specific enantiomer of a compound of general formula (I) isrequired, this may be obtained for example by resolution of acorresponding enantiomeric mixture of a compound of formula (I) usingconventional methods.

Thus, for example, specific enantiomers of the compounds of formula (I)may be obtained from the corresponding enantiomeric mixture of acompound of formula (I) using chiral HPLC procedure.

Alternatively, enantiomers of a compound of general formula (I) may besynthesised from the appropriate optically active intermediates usingany of the general processes described herein.

Thus, for example the required enantiomer may be prepared by thecorresponding chiral piperidin-4-one of formula (IV) using the processdescribed above for preparing compounds of formula (I) from compounds(IV), followed by separation of the diastereomeric mixture of a compoundof formula (I) using conventional procedure.

The chiral compounds (IV) may be prepared from the corresponding racemiccompound (IV) using conventional procedures such as salt formation witha suitable optically active acid, separating the resultantdiastereoisomeric salts by conventional means e.g. chromatography andcrystallisation followed by hydrolysis of the diastereoisomeric salts.

A suitable optically active acid for use in the process is L(+)mandelicacid.

In a further embodiment of the invention the enantiomers of the compoundof formula (I) may be prepared by reaction of a chiral amine (VI) usingany of the processes described above for preparing compounds of formula(I) from amine (V).

The chiral amine (III) may be prepared from the corresponding racemicamine (III) using any conventional procedures such as salt formationwith a suitable optically active acid.

The invention is further illustrated by the following Intermediates andExamples which are not intended as a limitation of the invention.

In the Intermediates and Examples unless otherwise stated:

Melting points (m.p.) were determined on a Buchi m.p. apparatus and areuncorrected. All temperatures refer to 0° C.

Infrared spectra (IR) were measures in chloroform or nujol solutions ona FT-IR instrument. Proton Magnetic Resonance (NMR) spectra wererecorded on Varian instruments at 400 or 500 MHz, chemical shifts arereported in ppm (δ) using the residual solvent line as internalstandard. Splitting patterns are designed as s, singlet; d, double; t,triple; q, quartet; m, multiplet; b, broad. Mass spectra (MS) were takenon a VG Quattro mass spectrometer. Optical rotations were determined at20° C. with a Jasco DIP 360 Instrument (1=10 cm, cell volume=1 mL, λ=589nm).

Flash silica gel chromatography was carried out over silica gel 230-400mesh supplied by Merck AG Darmstadt, Germany. T.l.c. refers to thinlayer chromatography on 0.25 mm silica gel plates (60F-254 Merck) andvisualised with UV light.

Solutions were dried over anhydrous sodium sulphate.

Methylene chloride was redistilled over calcium hydride andtetrahydrofuran was redistilled over sodium.

The following abbreviation are used in the text: AcOEt=ethyl acetate,CH=cyclohexane; DCM=methylene chloride, DMF=N,N′-dimethylformamide,DIPEA=N,N-diisopropylethylamine, Et2O=diethyl ether, EtOH=ethanol,MeOH=methanol, TEA=triethylamine, THF=tetrahydrofuran.

Diastereoisomer A refers to a mixture of compounds having anticonfiguration as defined above.

Diastereoisomer B refers to a mixture of compounds having synconfiguration as defined above.

Diastereoisomer 1 refers to a single diastereoisomer whose absoluteconfiguration has not determinated.

Diastereoisomer 2 refers to a single diastereoisomer whose absoluteconfiguration has not determinated.

Intermediate 11-(Benzyloxycarbonyl)-2-(4-fluoro-2-methyl-phenyl)-2,3-dihydro-4-pyridone

A small amount of iodine was added to a suspension of magnesium turnings(13.2 g) in dry THF (300 mL), at r.t., under a nitrogen atmosphere, thenthe mixture was vigorously refluxed for 20 minutes. To this suspension,a 15% of a solution of 2-bromo-5-fluoro-toluene (52.5 mL) in anhydrousTHF (300 mL) was added. The suspension was heated under vigorous refluxuntil the brown colour disappeared. The remaining part of the bromidesolution was added drop-wise over 1 hour to the refluxing suspensionwhich was then stirred for a further 1 hour. This solution of Grignardreagent was then added drop-wise to the pyridinium salt obtained frombenzyl chloroformate (48.7 mL) and 4-methoxypyridine (25 mL) in dry THF(900 mL) at −23° C.

The obtained solution was stirred 1 hour at −20° C. then it was warmedup to 20° C., a 10% hydrochloric acid solution (560 mL) was added andthe aqueous layer was extracted with AcOEt (2×750 mL).

The combined organic extracts were washed with 5% sodium hydrogencarbonate solution (600 mL) and brine (600 mL) then partiallyconcentrated in vacuo.

CH (400 mL) was added drop-wise over 1 hour at 20° C. and the resultingmixture was stirred 30 minutes and then filtered to give the titlecompound as a white solid (66 g).

IR (nujol): 1726 and 1655 (C═O), 1608(C═C) cm⁻¹. NMR (d₆-DMSO): δ (ppm)8.19 (d, 1H); 7.31-7.18 (m, 5H); 7.08 (m,2H); 6.94 (dt, 1H); 5.77 (d,1H); 5.36 (d, 1H); 5.16 (2d, 2H); 3.26 (dd, 1H); 2.32 (d, 1H); 2.26 (s,3H).

MS (ES/+): m/z=340 [MH]⁺.

Intermediate 2 2-(4-Fluoro-2-methyl-phenyl)-piperidine-4-one

Method A:

2-Fluoro-4-methyl-benzaldehyde (4 g) was added to a solution of4-aminobutan-2-one ethylene acetal (3.8 g) in dry benzene (50 mL) andthe solution was stirred at r.t. under a nitrogen atmosphere. After 1hour the mixture was heated at reflux for 16 hours and then allowed tocool to r.t. This solution was slowly added to a refluxing solution ofp-toluenesulphonic acid (10.6 g) in dry benzene (50 mL) previouslyrefluxed for 1 hour with a Dean-Stark apparatus. After 3.5 hours thecrude solution was cooled and made basic with a saturated potassiumcarbonate solution and taken up with AcOEt (50 mL). The aqueous phasewas extracted with AcOEt (3×50 mL) and Et2O (2×50 mL). The organic layerwas dried and concentrated in vacuo to a yellow thick oil as residue(7.23 g). A portion of the crude mixture (3 g) was dissolved in a 6Nhydrochloric acid solution (20 mL) and stirred at 60° C. for 16 hours.The solution was basified with solid potassium carbonate and extractedwith DCM (5×50 mL). The combined organic phases were washed with brine(50 mL), dried and concentrated in vacuo to give the title compound (2.5g) as a thick yellow oil.

Method B

L-selectride (1M solution in dry THF, 210 mL) was added drop-wise, over80 minutes, to a solution of intermediate 1 (50 g) in dry THF (1065 mL)previously cooled to −72° C. under a nitrogen atmosphere. After 45minutes, 2% sodium hydrogen carbonate solution (994 mL) was addeddrop-wise and the solution was extracted with AcOEt (3×994 mL). Thecombined organic phases were washed with water (284 mL) and brine (568mL). The organic phase was dried and concentrated in vacuo to get1-benzyloxycarbonyl-2-(4-fluoro-2-methyl-phenyl)-piperidine-4-one as apale yellow thick oil (94 g) which was used as a crude.

This material (94 g) was dissolved in AcOEt (710 mL), then 10% Pd/C(30.5 g) was added under a nitrogen atmosphere. The slurry washydrogenated at 1 atmosphere for 30 minutes. The mixture was filteredthrough Celite and the organic phase was concentrated in vacuo to givethe crude 2-(4-fluoro-2-methyl-phenyl)-piperidine-4-one as a yellow oil.This material was dissolved in AcOEt (518 mL) at r.t. and racemiccamphorsulphonic acid (48.3 g) was added. The mixture was stirred at r.tfor 18 hours, then the solid was filtered off, washed with AcOEt (2×50mL) and dried in vacuo for 18 hours to give2-(4-fluoro-2-methyl-phenyl)-piperidine-4-one, 10-camphorsulfonic acidsalt as a pale yellow solid (68.5 g). (M.p.: 167-169° C.-NMR (d₆-DMSO):δ (ppm) 9.43 (bs, 1H); 9.23 (bs, 1H); 7.66 (dd, 1H); 7.19 (m, 2H); 4.97(bd, 1H); 3.6 (m, 2H); 2.87 (m, 3H); 2.66 (m, 1H); 2.53 (m, 2H); 2.37(s+d, 4H); 2.22 (m, 1H); 1.93 (t, 1H); 1.8 (m, 2H); 1.26 (m, 2H); 1.03(s, 3H); 0.73 (s, 3H).

This material (68.5 g) was suspended in AcOEt (480 mL) and stirred witha saturated sodium hydrogen carbonate (274 mL). The organic layer wasseparated and washed with further water (274 mL). The organic phase wasdried and concentrated in vacuo to give the title compound (31 g) as ayellow-orange oil.

NMR (d₆-DMSO): δ (ppm) 7.49 (dd, 1H); 7.00 (m, 2H); 3.97 (dd, 1H); 3.27(m, 1H); 2.82 (dt, 1H); 2.72 (bm, 1H); 2.47 (m, 1H); 2.40 (m, 1H); 2.29(s, 3H); 2.25 (dt, 1H); 2.18 (m, 1H).

MS (ES/+): m/z=208 [MH]⁺.

Intermediate 32-(4-Fluoro-2-methyl-phenyl)-4-oxo-piperidine-1-carboxylic acid(3,5-bis-trifluoromethyl-benzyl)-methylamide

A solution of triphosgene (1.43 g) dissolved in dry DCM (10 mL) wasadded to a solution of intermediate 2 (2.5 g) and DIPEA (8.4 mL) in dryDCM (20 ML) previously cooled to 0° C. under a nitrogen atmosphere. Thesolution was stirred at 0° C. for 2 hours, then(3,5-bis-trifluoromethyl-benzyl)-methylamine hydrochloride (5.63 g) andDIPEA (3.34 mL) were added. The mixture was stirred under nitrogen atr.t. for 14 hours. The mixture was taken up with AcOEt (50 mL), washedwith cold 1N hydrochloric acid solution (3×20 mL) and brine (10 mL). Theorganic layer was dried and concentrated in vacuo to a residue which waspurified by flash chromatography (AcOEt/CH 3:7) to give the titlecompound as a white foam (3.85 g).

IR (nujol): 1721 and 1641 (C═O) cm⁻¹.

NMR (d₆-DMSO): δ (ppm) 7.96 (s, 1H); 7.76 (s, 2H); 7.25 (dd, 1H); 6.97(dd, 1H); 6.90 (dt, 1H); 5.22 (t, 1H); 4.59 (d, 1H); 4.43 (d, 1H);3.63-3.49 (m, 2H); 2.79 (s, 3H); 2.69 (m, 2H); 2.49 (m, 2H); 2.26 (s,3H).

MS (ES/+): m/z=491 [MH]⁺.

Intermediate 42-(R)-(4-Fluoro-2-methyl-phenyl)-4-oxo-piperidine-1-carboxylic acid[1-(R)-3,5-bis-trifluoromethyl-phenyl)-ethyl]-methylamide (4a) and2-(S)-(4-Fluoro-2-methyl-phenyl)-4-oxo-piperidine-1-carboxylic acid[1-(R)-3,5-bis-trifluoromethyl-phenyl)-ethyl]-methylamide (4b)

Method A:

A solution of triphosgene (147 mg) dissolved in dry DCM (5 mL) was addeddrop-wise to a solution of intermediate 2 (250 mg) and DIPEA (860 μL) indry DCM (15 mL) previously cooled to 0° C. under a nitrogen atmosphere.After 2 hours, [1-(R)-3,5-bis-trifluoromethyl-phenyl)-ethyl]-methylaminehydrochloride (503 mg) and DIPEA (320 μL) in dry-acetonitrile (20 mL)were added and the mixture was heated to 70° C. for 16 hours. Further[1-(R)-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-methylamine hydrochloride(170 mg) and DIPEA (100 μL) were added and the mixture was stirred at70° C. for further 4 hours. Next, the mixture was allowed to cool tor.t., taken up with AcOEt (30 mL), washed with a 1N hydrochloric acidcold solution (3×15 mL) and brine (2×10 mL). The organic layer was driedand concentrated in vacuo to a residue, which was purified by flashchromatography (CH/AcOEt 8:2) to give:

-   1. intermediate 4a (230 mg) as a white foam,-   2. intermediate 4b (231 mg) as a white foam.

Intermediate 4a

NMR (d₆-DMSO): δ (ppm) 7.98 (bs, 1H); 7.77 (bs, 2H); 7.24 (dd, 1H); 6.97(dd, 1H); 6.89 (m, 1H); 5.24 (t, 1H); 5.14 (q, 1H); 3.61 (m, 1H); 3.55(m, 1H); 2.71 (m, 2H); 2.56 (s, 3H); 2.50 (m, 2H); 2.26 (s, 3H); 1.57(d, 3H).

MS (ES/+): m/z=505 [MH]⁺.

Intermediate 4b

NMR (d₆-DMSO): δ (ppm) 7.96 (bs, 1H); 7.75 (bs, 2H); 7.24 (dd, 1H); 6.98(dd, 1H); 6.93 (dt, 1H); 5.29 (q, 1H); 5.24 (t, 1H); 3.56 (m, 1H); 3.48(m, 1H); 2.70 (s, 3H); 2.50 (m, 4H); 2.26 (s, 3H); 1.54 (d, 3H).

MS (ES/+): m/z=505 [MH]⁺.

Intermediate 4a

Method B

A saturated sodium hydrogen carbonate solution (324 mL) was added to asolution of intermediate 9 (21.6 g) in AcOEt (324 mL) and the resultingmixture was vigorously stirred for 15 minutes. The aqueous layer wasback-extracted with further AcOEt (216 mL) and the combined organicextracts were dried and concentrated in vacuo to give intermediate 8 asa yellow oil, which was treated with TEA (19 mL) and AcOEt (114 mL). Thesolution obtained was added drop-wise over 40 minutes to a solution oftriphosgene (8 g) in AcOEt (64 mL) previously cooled to 0° C. under anitrogen atmosphere, maintaining the temperature between 0° C. and 8° C.

After stirring for 1 hours at 0° C. and for 3 hours at 20° C.,[1-(R)-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-methylamine hydrochloride(29.7 g), AcOEt (190 mL) and TEA (38 mL) were added to the reactionmixture which was then heated to reflux for 16 hours. The solution waswashed with 10% sodium hydroxide solution (180 mL), 1% hydrochloric acidsolution (4×150 mL), water (3×180 mL) and brine (180 mL). The organiclayer was dried and concentrated in vacuo to a residue, which waspurified through a silica pad (CH/AcOEt 9:1) to give the title compound(21.5 g) as a brown thick oil.

NMR (d₆-DMSO): δ (ppm) 7.97-7.77 (bs+bs, 3H); 7.24 (dd, 1H); 6.97 (dd,1H); 6.88 (td, 1H); 5.24 (m, 1H); 5.14 (q, 1H); 3.58 (m, 2H); 2.7 (m,2H); 2.56 (s, 3H); 2.49 (m, 2H); 2.26 (s, 3H); 1.57 (d, 3H).

Intermediate 52-(S)-(4-Fluoro-2-methyl-phenyl)-4-oxo-piperidine-1-carboxylic acid[1-(S)-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-methylamide (5a) and2-(R)-(4-Fluoro-2-methyl-phenyl)-4-oxo-piperidine-1-carboxylic acid[1-(S)-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-methylamide (5b)

A solution of triphosgene (147 mg) dissolved in dry DCM (5 mL) was addedto a solution of intermediate 2 (250 mg) and DIPEA (860 μL) in dry DCM(15 mL) previously cooled to 0° C. under a nitrogen atmosphere. After 2hours, a solution of[1-(S)-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-methylamine hydrochloride(510 mg) and DIPEA (320 μL) in dry acetonitrile (20 mL) was added andthe mixture was heated to 70° C. for 16 hours. Then, further[1-(S)-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-methylamine hydrochloride(170 mg) and DIPEA (105 μL) were added. After further 4 hours at 70° C.,the mixture was allowed to cool to r.t., taken up with AcOEt (30 mL),washed with a 1N hydrochloric acid cold solution (3×15 mL) and brine(2×10 mL). The organic layer was dried and concentrated in vacuo to aresidue, which was purified by flash chromatography (CH/AcOEt 8:2) togive:

-   1. intermediate 5a (234 mg) as a white foam,-   2. intermediate 5b (244 mg) as a white foam.

Intermediate 5a

NMR (d₆-DMSO): δ (ppm) 7.98 (bs, 1H); 7.77 (bs, 2H); 7.24 (dd, 1H); 6.97(dd, 1H); 6.89 (m, 1H); 5.24 (t, 1H); 5.14 (q, 1H); 3.61 (m, 1H); 3.55(m, 1H); 2.71 (m, 2H); 2.56 (s, 3H); 2.50 (m, 2H); 2.26 (s, 3H); 1.57(d, 3H).

MS (ES/+): m/z=505 [MH]⁺.

Intermediate 5b

NMR (d₆-DMSO): δ (ppm) 7.96 (bs, 1H); 7.75 (bs, 2H); 7.24 (dd, 1H); 6.98(dd, 1H); 6.93 (dt, 1H); 5.29 (q, 1H); 5.24 (t, 1H); 3.56 (m, 1H); 3.48(m, 1H); 2.70 (s, 3H); 2.50 (m, 4H); 2.26 (s, 3H); 1.54 (d, 3H).

MS (ES/+): m/z=505 [MH]⁺.

Intermediates 62-(S)-(4-Fluoro-2-methyl-phenyl)-4-oxo-3,4-dihydro-2H-pyridine-1-carboxylicacid (1R, 2S, 5R)-2-isopropyl-5-methyl-cyclohexyl ester (6a) and2-(R)-(4-Fluoro-2-methyl-phenyl)-oxo-3,4-dihydro-2H-pyridine-1-carboxylicacid (1R, 2S, 5R)-2-isopropyl-5-methyl-cyclohexyl ester (6b)

A solution of 2-bromo-5-fluoro-toluene (3.68 g) in dry THF (10 mL) wasdropped over 30 minutes, into a mixture of magnesium (525 mg) and iodine(1 crystal) in dry THF (5 mL) previously heated to 70° C. under anitrogen atmosphere. The mixture was stirred at 70° C. for 1.5 hours,then allowed to cool to r.t.

A solution of (−)-mentyl chloroformate (3.53 mL) in dry THF (15 mL) wasadded to a solution of 4-methoxypyridine (1.52 mL) in dry THF (35 mL)previously cooled to −78° C. under a nitrogen atmosphere. After 15minutes, the solution containing the 4-fluoro-2-methyl-phenyl magnesiumbromide was added drop-wise, and the mixture was stirred at −78° C. for1 hour. The reaction was quenched by the addition of 1M hydrochloricacid solution (20 mL), warmed to r.t. and stirred at 23° C. for 30minutes. After extraction with AcOEt (2×150 mL), the combined organicextracts were washed with brine (50 mL), dried and concentrated in vacuoto a residue, which was purified by flash chromatography (CH/THF/toluene8:1:1) to give:

-   1. intermediate 6a (3.44 g—yellow oil)-   2. intermediate 6b (530 mg—white solid).

Intermediate 6a

T.l.c.: cyclohexane/THF/toluene 7:2:1, Rf=0.59.

IR (nujol): 1718 and 1675 (C═O) cm⁻¹.

NMR (d₆-DMSO): δ (ppm) 8.14 (d, 1H); 7.08 (dd, 1H); 7.02 (dd, 1H); 6.95(m, 1H); 5.68 (d, 1H); 5.34(d, 1H); 4.47 (m, 1H); 3.26 (dd, 1H); 2.30(m, 4H); 1.7 (m, 4H); 1.33 (m, 2H); 0.8 (m, 11H).

MS (ES/+): m/z=388 [MH]⁺.

Intermediate 6b

M.p.: 117-120° C.

T.l.c.: cyclohexane/THF/toluene 7:2:1, Rf=0.56.

IR (nujol): 1718 and 1669 (C═O) cm⁻¹.

NMR (d₆-DMSO): δ (ppm) 8.17 (d, 1H); 7.04-6.94 (m, 3H); 5.70 (d, 1H);5.35 (d, 1H); 4.42 (m, 1H); 3.26 (dd, 1H); 2.30 (m, 4H); 1.58-1.40 (m,3H); 1.2-0.7 (m, 8H); 0.51-0.34 (bs, 6H):

MS (ES/+): m/z=388 [MH]⁺.

Intermediate 72-(R)-(4-Fluoro-2-methyl-phenyl)-2,3-dihydro-1H-pyridin-4-one

Sodium methoxide (100 mg) was added to a solution of intermediate 6b(170 mg) in MeOH (15 mL) under a nitrogen atmosphere. The mixture wasrefluxed for two hours, and the solvent was removed in vacuo. Theresidue was partitioned between water (10 mL) and AcOEt (15 mL). Thelayers were separated, and the aqueous phase was extracted with furtherAcOEt (4×10 mL). The combined organic extracts were washed with brine(10 mL), dried and concentrated in vacuo to give the title compound (145mg) as a light yellow oil.

NMR (d₆-DMSO): δ (ppm) 7.71 (bd, 1H); 7.45 (dd, 1H); 7.38 (t, 1H); 7.03(m, 2H; 4.86 (dd, 1H); 4.77 (d, 1H); 2.42 (dd, 1H); 2.31 (m, 4H)

MS (ES/+): m/z=206 [M+H]⁺.

Intermediate 8 2-(R)-(4-Fluoro-2-methyl-phenyl)-piperidin-4-one

Palladium over charcoal (10%-74 mg) was added to a solution ofintermediate 7 (145 mg) in MeOH (8 mL) and THF (2 mL). The mixture wasallowed to react with hydrogen in a pressure reactor (2 atm) overnight.After flushing with nitrogen, the solution was filtered and the solventremoved in vacuo. The crude product was purified by flash chromatography(AcOEt/MeOH 9:1) to give the title compound (26 mg) as a yellow oil.

The enantiomeric excess (90-95%) was detected by chiral HPLC.

T.l.c.:AcOEt/MeOH 9:1, Rf=0.2.

NMR (d₆-DMSO): δ (ppm) 7.49 (dd, 1H); 7.00 (m, 2H); 3.97 (dd, 1H); 3.27(m, 1H); 2.82 (dt, 1H); 2.72 (bm, 1H); 2.47 (m, 1H); 2.40 (m, 1H); 2.29(s, 3H); 2.25 (dt, 1H); 2.18 (m, 1H).

MS (ES/+): m/z=208 [MH]⁺.

Intermediate 9 2-(R)-(4-Fluoro-2-methyl-phenyl)-piperidin-4-oneL-(+)-mandelate

A solution of L-(+)-mandelic acid (22.6 g) in AcOEt (308 mL) was addedto a solution of intermediate 2 (31 g) in AcOEt (308 mL). Thenisopropanol (616 mL) was added and the solution was concentrated invacuo to 274 mL. The solution was then cooled to 0° C. and further coldisopropanol (96 mL) was added. The thick precipitate was stirred undernitrogen for 5 hours at 0° C., then filtered and washed with cold Et2O(250 mL) to give the title compound as a pale yellow solid (20.3 g).

M.p.: 82-85° C.

NMR (d₆-DMSO): δ (ppm) 7.51 (dd, 1H); 7.40 (m, 2H); 7.32 (m, 2H); 7.26(m, 1H); 1H); 7.0 (m, 2H); 4.95 (s, 1H); 4.04 (dd, 1H); 3.31 (m, 1H);2.88 (m, 1H); 2.49-2.2 (m, 4H); 2.29 (s, 3H).

Chiral HPLC: HP 1100 HPLC system; column Chiralcel OD-H, 25 cm×4.6 mm;mobile phase: n-hexane/isopropanol 95:5+1% diethylamine; flow=1.3ml/min; λ=240/215 nm; retention time: 12.07 minutes.

Intermediate 102-(R)-4-Fluoro-2-methyl-phenyl)-4-oxo-piperidine-1carboxylic acid(3,5-bis-trifluoromethyl-benzyl)-methylamide

Method A

A solution of triphosgene (17 mg) in dry DCM (2 mL) was added to asolution of intermediate 8 (26 mg) and DIPEA (65 mg) in dry DCM (3 mL)previously cooled to 0° C. under a nitrogen atmosphere. After two hoursacetonitrile (10 mL) was added, the temperature was allowed to reachr.t. and the DCM evaporated under a nitrogen flush. Then, a solution of3,5-(bis-trifluoromethyl-benzyl)-methylamine hydrochloride (74 mg) andDIPEA (130 mg) in acetonitrile (3 mL) was added and the mixture wasstirred at 23° C. overnight. The solvent was concentrated in vacuo. Theresidue was dissolved in AcOEt (10 mL) and washed with 1N hydrochloricacid solution (3×5 mL), 5% sodium hydrogen carbonate (5 mL) and brine(10 mL). The organic layer was dried and concentrated in vacuo to aresidue, which was purified by flash chromatography (CH/AcOEt 1:1) togive the title compound (50 mg) as a white solid.

Method B

A saturated sodium hydrogen carbonate solution (348 mL) was added to asolution of intermediate 9 (23.2 g) in AcOEt (348 mL) and the resultingmixture was vigorously stirred for 15 minutes. The aqueous layer wasback-extracted with further AcOEt (230 mL) and the combined organicextracts were dried and concentrated in vacuo to give intermediate 8(12.31 g) as a yellow oil, which was treated with TEA (20.5 mL) andAcOEt (123 mL). The solution obtained was added drop-wise over 40minutes to a solution of triphosgene (8 g) in AcOEt (61 mL) previouslycooled to 0° C. under a nitrogen atmosphere, maintaining the temperaturebetween 0° C. and 8° C.

After stirring for 2 hours at 20° C.,3,5-(bis-trifluoromethyl-benzyl)-methylamine hydrochloride (28.1 g),AcOEt (184 mL) and TEA (33 mL) were added to the reaction mixture whichwas then further stirred for 2 hours at 20° C.

The solution was washed with 10% sodium hydroxide solution (3×185 mL)and 1% hydrochloric acid solution (3×185 mL). The organic layer wasdried and concentrated in vacuo to a crude (38 g), which was purifiedthrough a silica pad (CH/AcOEt from 9:1 to 1:1) to give the titlecompound (24.7 g) as a colourless oil.

NMR (d₆-DMSO): δ (ppm) 7.96 (s, 1H); 7.76 (s, 2H); 7.26 (dd, 1H); 6.98(dd, 1H); 6.90 (td, 1H); 5.23 (t, 1H); 4.61 (d, 1H); 4.41 (d, 1H); 3.60(m, 2H); 2.69 (m,2H); 2.79 (s, 3H); 2.50 (m, 2H); 2.27 (s,3H).

MS (ES/+): m/z=491 [MH]⁺.

Intermediate 112-(4-Fluoro-2-methyl-phenyl)-4-hydroxy-piperidine-1-carboxylic acid(3,5-bis-trifluoromethyl-benzyl)-methylamide

A solution of intermediate 3 (150 mg) and sodium borohydride (13 mg) indry MeOH (5 mL) was stirred at 0° C. for 2 hours under a nitrogenatmosphere. The crude solution was washed with a saturated ammoniumchloride solution (4 mL) and taken up with AcOEt (5 mL). The aqueousphase was extracted with AcOEt (3×5 mL) and the combined organic phaseswere washed with brine (5 mL). The organic layer was dried andconcentrated in vacuo to a residue which was purified by flashchromatography (AcOEt/CH 7:3) to give:

-   1. intermediate 11a (4 mg)-   2. intermediate 11b (30 mg).

Intermediate 11a (diastereoisomer A)

NMR (d₆-DMSO): δ (ppm) 7.94 (bs, 1H); 7.63 (bs, 2H); 7.22 (bs, 1H); 6.88(dd, 1H); 6.77 (dt, 1H); 4.69 (d, 1H); 4.60 (d, 1H); 4.36 (d, 1H); 4.13(dd, 1H); 3.94 (m, 1H); 3.57 (m, 1H); 2.88 (s, 3H); 2.65 (m, 1H); 2.48(s, 3H); 1.83 (m, 1H); 1.62 (m, 2H); 1.22 (m, 1H).

MS (ES/+): m/z=493 [MH]⁺, 475 [M-OH]⁺.

Intermediate 11b (diastereoisomer B)

NMR (d₆-DMSO): δ (ppm) 7.93 (bs, 1H); 7.58 (bs, 2H); 7.21 (dd, 1H); 6.88(dd, 1H); 6.77 (dt, 1H); 4.78 (d, 1H); 4.62 (d, 1H); 4.33 (d, 1H); 4.13(dd, 1H); 3.58 (m, 1H); 3.37 (m, 1H); 2.90 (s, 3H); 2.67 (m, 1H); 2.32(s, 3H); 1.89 (m, 1H); 1.83 (m, 1H); 1.52 (dq, 1H); 1.29 (q, 1H).

MS (ES/+): m/z=493 [MH]⁺, 475 [M-OH]⁺.

Intermediate 12 (4-Fluoro-2-methyl-phenylamino)-acetic acid ethyl ester

A solution of ethyl glyoxalate (50% solution in toluene—40.8 mL) intoluene (180 mL) was heated to reflux for 1.5 hours under a Nitrogenatmosphere, in a flask equipped with a Dean Stark apparatus. Then, asolution of 4-fluoro-2-methyl-aniline (10 g) in dry toluene (20 mL) wasslowly added. The mixture was heated to reflux for 3 hours, then it wasconcentrated in vacuo. The residue was purified by flash chromatography(toluene/CH/AcOEt 4:4:2) to give the title compound (13.06 g) as ayellow oil.

T.l.c.: toluene/CH/AcOEt 4:4:2, Rf=0.67.

NMR (CDCl3): δ (ppm) 7.8 (s, 1H); 6.95 (d, 1H); 6.85 (d, 2H); 4.4 (q,2H); 2.35 (s, 3H); 3.3 (t 3H).

MS (ES/+): m/z=210 [M+H]⁺.

Intermediate 131-(4-(Fluoro-2-methyl-phenyl)-4-oxo-1,2,3,4-tetrahydro-pyridine-2-carboxylicacid ethyl ester

Boron trifluoride etherate (1.22 mL) was added to a solution ofintermediate 12 (2 g) in anhydrous DCM (20 mL) previously cooled to −78°C. under a Nitrogen atmosphere. After stirring for 15 minutes at −78°C., the 1-methoxy-3-trimethylsiloxy-1,3-butadiene (2.67 mL) was droppedover 45 minutes. The resulting solution was stirred at −78° C. for 2hours, then TFA (0.74 mL) was added. The mixture was stirred at 0° C.for 15 minutes, then a saturated sodium hydrogen carbonate solution wasadded and the mixture was extracted with AcOEt (3×50 mL). The combinedorganic extracts were dried and concentrated in vacuo to give a residue,which was purified by flash chromatography (CH/AcOEt from 8:3 to 7:3) togive the title compound (1.5 g) as a pale yellow solid.

T.l.c.: CH/AcOEt 6:4, Rf=0.2.

NMR (CDCl3): δ (ppm) 7.4 (dd, 1H); 7.1 (d, 1H); 7.0-6.8 (m, 2H); 5.15(d, 1H); 4.4 (m, 1H); 4.1 (m, 2H); 3.1-2.85 (m, 2H); 2.4 (s, 3H); 1.15(t, 3H).

Intermediate 141-(4-Fluoro-2-methyl-phenyl)-4-oxo-piperidine-2-carboxylic acid ethylester

L-selectride (1M solution in dry THF, 3.96 mL) was added drop-wise, over1 hour, to a solution of intermediate 13 (1 g) in dry THF (30 mL)previously cooled to −78° C. under a Nitrogen atmosphere. After 1 hour,a saturated sodium hydrogen carbonate solution (20 mL) was addeddrop-wise and the solution was extracted with AcOEt (3×50 mL). Thecombined organic extracts were dried and concentrated in vacuo to aresidue, which was purified by flash chromatography (CH/AcOEt 8:2) togive the title compound (810 mg) as a white solid.

T.l.c.: CH/AcOEt 6:4, Rf=0.6.

NMR (CDCl3): δ (ppm) 7.4 (dd, 1H); 7.1 (dd, 1H); 6.9 (dd, 1H); 6.8 (dt,1H); 4.2 (q, 2H); 4.15 (m, 1H); 3.6 (m, 1H); 3.2 (m, 1H); 2.8-2.7 (dd,2H); 2.6 (m, 2H); 2.4 (s, 3H); 1.2 (t, 3H).

Intermediate 151-(4-Fluoro-2-methyl-phenyl)-4-oxo-piperidine-2carboxylic acid

Lithium hydroxide monohydrate (241 mg) was added to a solution ofintermediate 14 (300 mg) in MeOH (15 mL) and water (3 mL) and theresulting solution was stirred at 80° C. for 1 hour. The solution wasallowed to cool to r.t. and extracted with Et2O. The aqueous layer wasacidified until pH=6 with acetic acid and extracted with AcOEt (3×15mL). The combined organic extractes were dried and concentrated in vacuoto give the title compound (230 mg) as yellow solid, which was usedwithout any further purification in the next step.

MS (ES/+): m/z=252 [M+H]⁺.

Intermediate 161-(4-Fluoro-2-methyl-phenyl)-4-oxo-piperidine-2-carboxylic acid(3,5-dichloro-benzyl)-methylamide

DIPEA (0.47 mL) and O-(benzotriazol-1-yl)-N,N,N′N′-tetramethyluroniumtetrafluoroborate (385.3 mg) were added to a solution of intermediate 16(230 mg) in anhydrous DMF (20 mL) under a Nitrogen atmosphere. Afterstirring for 15 minutes, (3,5-dichlorobenzyl)-methylamine hydrochloride(225 mg) was added and the mixture was stirred at r.t. for 4 hours. Thesolution was diluted with water (30 mL) and extracted with AcOEt (3×60mL). The combined organic extracts were washed with cold water (50 mL)and brine (3×80 mL), then concentrated in vacuo. The residue waspurified by flash chromatography (CH/AcOEt 1:1) to give the titlecompound (176 mg) as a pale yellow solid.

T.l.c.: CH/AcOEt 3:7, Rf=0.52.

NMR (d₆-DMSO): δ (ppm) 7.5-7.45 (2t, 1H); 7.14-6.88 (2d, 2H); 7.05 (dd,1H); 6.92 (dd, 1H); 6.82 (dt, 1H); 4.66-4.51 (2m, 1H); 4.59 (d, 1H);4.15-4.1 (d+m, 1H); 3.83-3.57 (2m, 1H); 3.05 (m, 1H); 2.73 (m, 1H); 2.51(m, 1H); 2.4-2.25 (m, 2H); 2.66-2.37 (2s, 3H); 2.37-2.24 (2s, 3H).

MS (ES/+): m/z=423 [M+H]⁺.

Intermediate 171-(4-Fluoro-2-methyl-phenyl)-4-oxo-piperidine-2-carboxylic acid[1-(R)-3,5-bis-trifluoromethyl-phenyl)-ethyl]-methylamide(17a—diastereoisomer 1) and1-(4-Fluoro-2-methyl-phenyl)-4-oxo-piperidine-2-carboxylic acid[1-(R)-3,5-bis-trifluoromethyl-phenyl)-ethyl]-methylamide(17b—diastereoisomer 2)

DIPEA (0.531 mL) and O-(benzotriazol-1-yl)-N,N,N′N′-tetramethyluroniumtetrafluoroborate (423 mg) were added to a solution of intermediate 15(298 mg) in anhydrous DMF (15 mL) under a Nitrogen atmosphere and theresulting solution was stirred at r.t for 15 minutes.

At the same time,[1-(R)-3,5-bis-trifluoromethyl-phenyl)-ethyl]-methylamine maleate (500mg) was treated with a saturated sodium hydrogen carbonate solution (10ML) and extraction with AcOEt (2×30 mL); the organic layer was dried andconcentrated in vacuo to give[1-(R)-3,5-bis-trifluoromethyl-phenyl)-ethyl]-methylamine (303 mg). Thisintermediate was added to the previous solution and the mixture wasstirred at 23° C. for 36 hours.

The solution was diluted with water (30 mL) and extracted with AcOEt(3×60 mL). The combined organic extracts were washed with cold water(2×50 mL) and brine (2×50 mL), dried and concentrated in vacuo. Theresidue was purified by flash chromatography (CH/AcOEt 1:1) to give:

-   1. intermediate 17a (56 mg) as yellow oil.-   2. intermediate 17b (36 mg) as yellow oil.

Intermediate 17a

T.l.c.: CH/AcOEt 1:1, Rf=0.6.

NMR (d₆-DMSO): δ (ppm) 7.95 (s, 1H); 7.72 (s, 2H); 7.02 (m, 2H); 6.94(m, 1H); 5.71 (q, 1H); 4.62 (m, 1H); 3.55 (m, 1H); 3.01 (m, 1H); 2.67(m, 1H); 2.34-2.17 (m, 4H); 2.04 (s, 3H); 1.33 (d, 3H).

Intermediate 17b

T.l.c.: CH/AcOEt 1:1, Rf=0.4.

NMR (d₆-DMSO): δ (ppm) 8.02 (bs, 1H); 7.76 (bs, 2H); 6.95 (dd, 1H); 6.69(dt, 1H); 6.46 (dt, 1H); 5.76 (q, 1H); 4.56 (m, 1H); 3.52 (m, 1H); 3.0(m, 1H); 2.68 (m, 1H); 2.44 (m, 1H); 2.26 (m, 5H); 2.15 (s, 3H); 1.4 (d,3H).

Intermediate 18

1-(4-Fluoro-2-methyl-phenyl)-4-oxo-piperidine-2-carboxylic acid(3,5-bis-trifluoromethyl-benzyl)-methylamide

DIPEA (2.6 mL) and O-(benzotriazol-1-yl)-N,N,N′N′-tetramethyluroniumhexafluorophosphate (2.48 g) were added to a solution of intermediate 15(1.259 g) in anhydrous DMF (25 mL) under a Nitrogen atmosphere. Afterstirring 30 minutes, (3,5-bis-trifluoromethyl-benzyl)-methylaminehydrochloride (1.62 g) was added and the mixture was stirred at r.t. for16 hours. The reaction mixture was diluted with AcOEt (50 mL) and washedwith a saturated ammonium chloride solution (30 mL), a saturated sodiumhydrogen carbonate solution (30 mL) and brine (3×50 mL). The organicextracts were dried and concentrated in vacuo. The residue was purifiedby flash chromatography (CH/AcOEt 9:1) to give the title compound (1.59g) as a dark yellow oil.

T.l.c.: CH/AcOEt 1:1, Rf=0.25.

NMR (d₆-DMSO): δ (ppm) 8.03 (bs, 1H); 7.84 (bs, 2H); 7.03 (dd, 1H); 6.79(dd, 1H); 6.64 (td, 1H); 4.80 (d, 1H); 4.67 (m, 1H); 4.29 (d, 1H); 3.55(m, 1H); 3.04 (m, 1H); 2.74 (m, 1H); 2.5 (m, 1H); 2.4-2.2 (m, 2H); 2.40(s, 3H); 2.38 (s, 3H).

MS (ES/+): m/z=491 [M+H]⁺.

EXAMPLE 14-(R,S)-(2,2,2-Trifluoroethyl)-amino-2-(R)-(4-fluoro-2-methyl-phenyl)-piperidine-1-carboxylicacid [1-(R)-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-methylamidehydrochloride

A solution of intermediate 4a (120 mg), 2,2,2-trifluoroethylamine (190μL) in dry 1,2-dichloroethane (10 mL) was stirred at 23° C. for 1 hoursunder a nitrogen atmosphere, then sodium triacetoxyborohydride (75.7 mg)was added. The mixture was stirred at 23° C. for 18 hours, then further2,2,2-trifluoroethylamine (190 μL) and few drops of acetic acid wereadded and the solution was stirred for further 24 hours. The solutionwas washed with a 5% sodium hydrogen carbonate solution (10 mL) andbrine (10 mL). The organic layer was dried and concentrated in vacuo toa residue that was purified by flash chromatography (CH/AcOEt 6:4) togive the4-(2,2,2-trifluoroethyl)amino-2-(R)-(4-fluoro-2-methyl-phenyl)-piperidine-1-carboxylicacid [1-(R)-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-methylamide (27mg—T.l.c.: CH/AcOEt 1:1 Rf=0.77) as an enantiomeric mixture in ratio C-2and C-4 anti/syn 4:6.

This material (25 mg) was dissolved in dry Et2O (5 mL) and treated withhydrochloric acid (1M in Et2O—1 mL). The resulting mixture was stirredat 23° C. for 30 minutes, then concentrated in vacuo to give the titlecompound as a whitish solid (25 mg).

M.p.: 116-7° C.

IR (nujol): 1659 and 1651 (C═O) cm⁻¹.

NMR (d₆-DMSO): δ (ppm) 7.91 (s, 1H); 7.73 (s, 1H); 7.68 (s, 1H); 7.23and 7.17 (2dd, 1H); 6.74-6.76 (m, 2H); 5.3 and 5.18 (2q, 1H); 4.9 and4.18 (m and dd, 1H); 3.5-3.1 (m, 3H); 2.74 and 2.65 (2s, 3H); 2.35 and2.28 (2s, 3H); 2.1-1.5 (m, 4H); 1.5 and 1.46 (2d, 3H).

MS (ES/+): m/z=588 [MH—HCl]⁺.

EXAMPLE 24-(R)-(2,2-Dimethyl-propylamino)-2-(R)-(4-fluoro-2-methyl-phenyl)-piperidine-1-carboxylicacid, [1-(R)-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-methylamidehydrochloride (2a)4-(S)-(2,2-Dimethyl-propylamino)-2-(R)-(4-fluoro-2-methyl-phenyl)-piperidine-1-carboxylicacid, [1-(R)-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-methylamidehydrochloride (2b)

A solution of intermediate 4a (120 mg), 2,2-dimethyl-propylamine (20.9mg) and sodium triacetoxyborohydride (78.2 mg) in dry 1,2-dichloroethane(5 mL) was stirred at 23° C. for 2 hours under a nitrogen atmosphere.The solution was washed with a 5% sodium hydrogen carbonate solution (10mL) and brine (10 mL). The organic layer was dried and concentrated invacuo to a residue that was purified by flash chromatography (AcOEt/MeOH85:15) to give three fractions:

-   1. diastereoisomer 1 (65.4 mg—T.l.c.: AcOEt/MeOH 7:3 Rf=0.41),-   2. a mixture of the two diastereoisomers (15.0 mg)-   3. diastereoisomer 2 (22.0 mg—T.l.c.: AcOEt/MeOH 7:3 Rf=0.39).

EXAMPLE 2a

A solution of diastereoisomer 1 (64.0 mg) in Et2O (5 mL) was treatedwith hydrochloric acid (1M in Et2O—1 mL). The resulting solution wasstirred at 23° C. for 30 minutes, then it was concentrated in vacuo togive the title compound as a white solid (67.4 mg).

IR (nujol): 3376 (NH₂ ⁺), 1627 (C═O) cm⁻¹.

NMR (d₆-DMSO): δ (ppm) 8.16,8.10 (2bm, 2H); 7.99 (s, 1H); 7.78 (s, 2H);7.39 (dd, 1H); 7.00 (dd, 1H); 6.93 (dt, 1H); 5.24 (t, 1H); 5.09 (q, 1H);3.54 (m, 2H); 3.05 (t, 1H); 2.81 (m, 2H); 2.60 (s, 3H); 2.31 (m, 1H);2.20 (s, 3H); 2.13 (m, 2H); 1.57 (d, 3H); 1.62 (m, 1H); 0.98 (s, 9H).

MS (ES/+): m/z=576 [MH—HCl]⁺.

EXAMPLE 2b

A solution of diastereoisomer 2 (21.0 mg) in dry Et2O (5 mL) was treatedwith hydrochloric acid (1M in Et2O—1 mL). The resulting mixture wasstirred at 23° C. for 15 minutes, then filtered and further treated withdry Et2O to give the title compound as a whitish solid (11 mg).

NMR (d₆-DMSO): δ (ppm) 7.99 (bs, 3H); 7.67 (bs, 1H); 7.16 (m, 1H); 6.96(m, 1H); 6.95 (m, 1H); 5.29 (m, 1H); 4.20 (m, 1H); 3.5-2.7 (m, 5H); 2.62(s, 3H); 2.35 (s, 3H); 2.7-2.0 (m, 4H); 1.45 (d, 3H); 0.95 (s, 9H).

MS (ES/+): m/z=576 [MH—HCl]⁺.

EXAMPLE 34-(R)-Ethylamino-2-(R)-(4-fluoro-2-methyl-phenyl)-piperidine-1-carboxylicacid [1-(R)-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-methylamidehydrochloride (3a) and4-(S)-Ethylamino-2-(R)-(4-fluoro-2-methyl-phenyl)-piperidine-1-carboxylicacid [1-(R)-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-methylamidehydrochloride (3b)

A suspension of intermediate 4a (100 mg), ethylamine hydrochloride (326mg), TEA (613 μL) and sodium triacetoxyborohydride (63 mg) in dry1,2-dichloroethane (2.5 mL) was stirred at 23° C. for 6 hours under anitrogen atmosphere. The solution was diluted with DCM (10 ml) washedwith 5% sodium hydrogen carbonate solution (10 mL) and brine (10 mL).The organic layer was dried and concentrated in vacuo to a residue whichwas purified by flash chromatography (AcOEt/MeOH 9:1) to give twofractions:

-   1. diastereoisomer 1 (50 mg—T.l.c. AcOEt/MeOH 8:2 Rf=0.2)-   2. diastereoisomer 2 (10 mg—T.l.c. AcOEt/MeOH 8:2 Rf=0.13)

EXAMPLE 3a

A solution of diastereoisomer 1 (50 mg) in dry Et2O (5 mL) was treatedwith hydrochloric acid (1M in Et2O—2 mL) and the resulting solution wasstirred at 23° C. for 30 minutes, then it was concentrated in vacuo. Theresidue was triturated with Et2O to give the title compound as a whitesolid (24 mg).

NMR (d₆-DMSO): δ (ppm) 8.56 (bs, 2H); 7.99 (s, 1H); 7.75 (s, 2H); 7.32(dd, 1H); 6.98 (dd, 1H); 6.90 (m, 1H); 5.12 (q, 1H); 5.04 (t, 1H);3.6-3.4 (m, 2H); 3.13 (t, 1H); 2.97 (m, 2H); 2.61 (s, 3H); 2.25 (s, 3H);2.10 (m, 2H); 1.98 (m, 1H); 1.65 (m, 1H); 1.55 (d, 3H); 1.19 (t, 3H).

MS (ES/+): m/z=534 [MH—HCl]⁺.

EXAMPLE 3b

A solution of diastereoisomer 2 (10 mg) in dry Et2O (2 mL) was treatedwith hydrochloric acid (1M in Et2O—0.5 mL). The resulting mixture wasstirred at 23° C. for 30 minutes, then it was concentrated in vacuo. Theresidue was triturated with Et2O to give the title compound as a whitesolid (7 mg).

NMR (d₆-DMSO): δ (ppm) 8.60 (bs, 2H); 7.99 (s, 1H); 7.67 (s, 2H); 7.15(dd, 1H); 6.94 (dd, 1H); 6.83 (dt, 1H); 5.29 (q, 1H); 4.19 (dd, 1H);3.43 (bd, 1H); 3.30 (m, 1H); 2.97 (bm, 2H); 2.80 (t, 1H); 2.74 (s, 3H);2.35 (s, 3H); 2.11 (bd, 1H); 2.06 (bd, 1H); 1.68 (m, 1H); 1.57 (m, 1H);1.45 (d, 3H); 1.17 (t, 3H).

MS (ES/+): m/z=534 [MH—HCl]⁺.

EXAMPLE 44-(R)-Dimethylamino-2-(R)-(4-fluoro-2-methyl-phenyl)-piperidine-1-carboxylicacid [1-(R)-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-methylamidehydrochloride (4a) and4-(S)-Dimethylamino-2-(R)-(4-fluoro-2-methyl-phenyl)-piperidine-1-carboxylicacid [1-(R)-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-methylamidehydrochloride (4b)

A solution of intermediate 4a (93 mg), dimethylamine (2 M in THF—40 μL)and sodium triacetoxyborohydride (57 mg) in dry 1,2-dichloroethane (10mL) was stirred at 23° C. for 6 hours under a nitrogen atmosphere. Thesolution was washed with a 5% sodium hydrogen carbonate solution (10 mL)and brine (10 mL). The organic layer was dried and concentrated in vacuoto a residue which was purified by flash chromatography (AcOEt/MeOH 95:5to 80:20) to give two fractions:

-   1. diastereoisomer 1 (39 mg—T.l.c.: AcOEt/MeOH 8:2 Rf=0.2),-   2. diastereoisomer 2 (26 mg—T.l.c.: AcOEt/MeOH 8:2 Rf=0.15).

EXAMPLE 4a

A solution of diastereoisomer 1 (39 mg) in dry Et2O (5 mL) was treatedwith hydrochloric acid (1M in Et2O—2 mL) and the resulting solution wasstirred at 23° C. for 5 minutes. The solution was concentrated in vacuoto give a white solid that was triturated in Et2O (2 mL), then filteredto give the title compound as a white solid (16 mg).

IR (nujol): 3443 (NH₂ ⁺, 1640 (C═O) cm⁻¹.

NMR (d₆-DMSO): δ (ppm) 9.64 (bs, 1H); 7.99 (s, 1H); 7.76 (s, 2H); 7.35(dd, 1H); 7.00 (dd, 1H); 6.92 (bt, 1H); 5.19 (bt, 1H); 5.07 (q, 1H);3.58 (m, 1H); 3.17 (t, 1H); 2.77 (bs, 3H); 2.73 (bs, 3H); 2.55 (s, 3H);2.21 (s+m, 3H+1H); 2.07 (bm, 2H); 1.63 (dq, 1H); 1.55 (d, 3H).

MS (ES/+): m/z=534 [MH—HCl]⁺.

EXAMPLE 4b

A solution of diastereoisomer 2 (26 mg) in dry Et2O (5 mL) was treatedwith hydrochloric acid (1M in Et2O—2 mL) and the resulting solution wasstirred at 23° C. for 5 minutes. The solution was concentrated in vacuoto give a white solid that was triturated in Et2O (2 mL), then filteredto give the title compound as a white solid (24 mg).

IR (nujol): 3399 (NH₂ ⁺), 1665 (C═O) cm⁻¹.

NMR (d₆-DMSO): δ (ppm) 9.75 (bs, 1H); 7.99 (s, 1H); 7.67 (s, 2H); 7.22(dd, 1H); 6.93 (dd, 1H); 6.81 (dt, 1H); 5.31 (q, 1H); 4.17 (dd, 1H);3.44 (m, 2H); 2.76 (t, 1H); 2.73 (s, 3H); 2.72 (s, 3H+3H); 2.35 (s, 3H);2.08 (d, 1H); 2.01 (d, 1H); 1.85 (dq, 1H); 1.64 (q, 1H); 1.46 (d, 3H)

EXAMPLE 54-(R)-Dimethylamino-2-(R)-(4-fluoro-2-methyl-phenyl)-piperidine-1-carboxylicacid (3,5-bis-trifluoromethyl-benzyl)-methylamide hydrochloride (5a) and4-(S)-Dimethylamino-2-(R)-(4-fluoro-2-methyl-phenyl)-piperidine-1-carboxylicacid (3,5-bis-trifluoromethyl-benzyl)-methylamide hydrochloride (5b)

A solution of intermediate 10 (1.0 g) and dimethylamine (2 M in THF) (50mL) in MeOH (40 mL) was stirred at 23° C. for 5 hours, then a solutionof sodium borohydride (85 mg) in dry MeOH (10 mL) was added. Theresulting mixture was stirred at 23° C. for 30 minutes, then a 5%solution of sodium hydrogen carbonate (20 mL) was added. The mixture wasconcentrated in vacuo to eliminate the alcohol, then the aqueous phasewas extracted with AcOEt (3×50 mL). The combined organic extracts weredried and concentrated in vacuo to a residue which was purified by flashchromatography (AcOEt/MeOH 7:3) to give three fractions:

-   1. diastereoisomer 1 (61 mg as a white solid T.l.c.: AcOEt/MeOH 8:2,    Rf=0.23)-   2. mixture of the two diastereoisomers (190 mg)-   3. diastereoisomer 2 (436 mg as a white solid—T.l.c.: AcOEt/MeOH    8:2, Rf=0.2).

EXAMPLE 5a

A solution of diastereoisomer 1 (61 mg) in dry Et2O (5 mL) was treatedwith hydrochloric acid (1M in Et2O—0.12 mL). The resulting mixture wasstirred at 0° C. for 15 minutes, then filtered to give the titlecompound as a white solid (55 mg).

M.p.: 180-3° C.

NMR (d₆-DMSO): δ (ppm) 9.78 (bs, 1H); 7.97 (s, 1H); 7.79 (s, 2H); 7.35(dd, 1H); 7.0 (dd, 1H); 6.92 (dt, 1H); 5.17 (bt, 1H); 4.56 (d, 1H); 4.41(d, 1H); 3.56 (bm, 2H); 3.1 (t, 1H); 2.75 (m+s, 9H); 2.23 (s, 4H); 2.09(bm, 2H); 1.66 (m, 1H).

MS (ES/+): m/z=520 [M-Cl]⁺.

EXAMPLE 5b

A solution of diastereoisomer 2 (436 mg) in dry Et2O (25 mL) was treatedwith hydrochloric acid (1M in Et2O—0.85 mL). The resulting mixture wasstirred at 0° C. for 15 minutes, then filtered to give the titlecompound (380 mg) as a white solid.

M.p.: 147-150° C.

IR (nujol): 3406 (NH₂ ⁺), 1656 (C═O) cm⁻¹.

NMR (d₆-DMSO): δ (ppm) 9.87 (bs, 1H); 7.95 (s, 1H); 7.59 (s, 2H); 7.27(dd, 1H); 6.94 (dd, 1H); 6.82 (m, 1H); 4.63 (d, 1H); 4.37 (d, 1H); 4.2(dd, 1H); 3.54 (m, 1H); 3.3 (m, 1H); 2.92 (s, 3H); 2.70 (m, 6H); 2.70(m, 1H); 2.36 (s, 3H); 2.1-2.00 (m, 2H); 1.85 (m, 1H); 1.6 (m, 1H).

MS (ES/+): m/z=520 [M-Cl]⁺.

[α]_(D)=−82.77 (1.07% in DMSO).

EXAMPLE 64-(R)-(2-Fluoroethyl)-amino-2-(R)-(4-fluoro-2-methyl-phenyl)-piperidine-1-carboxylicacid [1-(R)-(3,5-bis)-trifluoromethyl-phenyl)-ethyl]-methylamidehydrochloride (6a) and4-(S)-(2-Fluoroethyl)-amino-2-(R)-(4-fluoro-2-methyl-phenyl)-piperidine-1-carboxylicacid [1-(R)-(3,5-bis)trifluoromethyl-phenyl)-ethyl]-methylamidehydrochloride (6b)

A suspension of intermediate 4a (100 mg), 2-fluoroethylaminehydrochloride (98 mg), TEA (100 μL) and sodium triacetoxyborohydride (65mg) in dry 1,2-dichloroethane (8 mL) was stirred at 23° C. for 2 hoursunder a nitrogen atmosphere. A further amount of 2-fluoroethylaminehydrochloride (98 mg) and TEA (100 μL) were added and the mixturestirred for 2 hours at 23° C. A further amount of sodiumtriacetoxyborohydride (65.0 mg) was added and the mixture stirred at 23°C. for 1.5 hours under a nitrogen atmosphere.

The solution was washed with a saturated sodium hydrogen carbonatesolution (8 mL) and brine (8 mL). The organic layer was dried andconcentrated in vacuo to a residue that was purified by flashchromatography (AcOEt/MeOH 95:5) to give two fractions:

-   1. diastereoisomer 1 (26.0 mg—T.l.c.: AcOEt/MeOH 8:2 Rf=0.44)-   2. diastereoisomer 2 (17.0 mg—T.l.c.: AcOEt/MeOH 8:2 Rf=0.3).

EXAMPLE 6a

A solution of diastereoisomer 1 (26.0 mg) in dry Et2O (1 mL) was treatedwith hydrochloric acid (1M in Et2O—20 μL), and the resulting solutionwas stirred at 0° C. for 15 minutes. The solution was concentrated invacuo and the residue was triturated with n-pentane (1 mL) to give thetitle compound as a white solid (21 mg).

NMR (d₆-DMSO): δ (ppm) 8.96 (bs, 2H); 7.99 (s, 1H); 7.75 (s, 2H); 7.34(dd, 1H); 7.00 (dd, 1H); 6.91 (m, 1H); 5.16-5.06 (m, 2H); 4.84-4.6 (m,2H); 3.64-3.10 (m, 5H); 2.3-1.65 (m, 4H); 2.60 (s, 3H); 2.24 (s, 3H);1.55 (d, 3H).

MS (ES/+): m/z=552 [MH—HCl]⁺.

EXAMPLE 6b

A solution of diastereoisomer 2 (17.0 mg) in dry Et2O (1 mL) was treatedwith hydrochloric acid (1M in Et2O—20 μL), and the resulting solutionwas stirred at 0° C. for 15 minutes. The solution was concentrated invacuo and the residue was triturated with n-pentane (1 mL) to give thetitle compound as a white solid (15 mg).

NMR (d₆-DMSO): δ (ppm) 8.93 (s, 2H); 7.99 (s, 1H); 7.67 (s, 2H); 7.15(dd, 1H); 6.94 (dd, 1H); 6.83 (m, 1H); 5.28 (q, 1H); 4.8-4.6 (m, 2H);4.18 (dd, 1H); 3.4 (m, 3H); 2.8-2.7 (m, 2H); 2.2-2.0 (m, 2H); 1.8-1.5(m, 2H); 2.73 (s, 3H); 2.34 (s, 3H); 1.45 (d, 3H).

MS (ES/+): m/z=552 [MH—HCl]⁺.

EXAMPLE 74-(R)-(2-Fluoro-ethylamino)-2-(R)-(4-fluoro-2-methyl-phenyl)-piperidine-1-carboxylicacid (3,5-bis-trifluoromethyl-benzyl)-methylamide hydrochloride (7a) and4-(S)-(2-Fluoro-ethylamino)-2-(R)-(4-fluoro-2-methyl-phenyl)-piperidine-1-carboxylicacid (3,5-bis-trifluoromethyl-benzyl)-methylamide hydrochloride (7b)

A mixture of intermediate 10 (65 mg), 2-fluoroethylamine hydrochloride(132 mg), TEA (184 μL) and sodium triacetoxyborohydride (42 mg) in dryacetonitrile (5 mL) was stirred at r.t. under a nitrogen atmosphere.After 6 hours further 2-fluoroethylamine hydrochloride (264 mg), TEA(368 μL) and sodium triacetoxyborohydride (15 mg) were added. Afterstirring at r.t. for 20 hours, the crude solution was quenched with a 5%sodium hydrogen carbonate solution (4 mL) and taken up with AcOEt (5mL). The aqueous phase was extracted with AcOEt (3×5 mL) and thecombined organic phases were washed with brine (5 mL). The organic layerwas dried and concentrated in vacuo to a residue which was purified byflash chromatography (AcOEt/MeOH 95:5) to give two fractions:

-   1. diastereoisomer 1 (35 mg—T.l.c. AcOEt/MeOH 9:1 Rf=0.4)-   2. diastereoisomer 2 (32 mg—T.l.c. AcOEt/MeOH 9:1 Rf=0.27).

EXAMPLE 7a

A solution of diastereoisomer 1 (30 mg) in dry Et2O (5 mL) was treatedwith hydrochloric acid (1M in Et2O—0.5 mL) at 0° C. and the resultingsolution was stirred under a nitrogen atmosphere for 30 minutes. Thesolution was concentrated in vacuo and the residue was triturated withEt2O to give the title compound as a whitish solid (26 mg).

M.p.: 145-6° C.

IR (nujol): 3404 (NH₂ ⁺), 1629 (C═O) cm⁻¹.

NMR (d₆-DMSO): δ (ppm) 9.04 (bs, 2H); 7.99 (s, 1H); 7.77 (s, 2H); 7.35(dd, 1H); 6.99 (dd, 1H); 6.91 (dt, 1H); 5.09 (bt, 1H); 4.75 (bd, 2H);4.58 (d, 1H); 4.43 (d, 1H);. 3.64 (bm, 1H); 3.45-3.3 (m, 3H); 3.11 (dd,1H); 2.81 (s, 3H); 2.27 (s, 3H); 2.17 (bm, 1H); 2.1 (bm, 2H); 1.69 (m,1H).

MS (ES/+): m/z=538 [MH—HCl]⁺.

EXAMPLE 7b

A solution of diastereoisomer 2 (32 mg) in dry Et2O (2 mL) was treatedwith hydrochloric acid (1M in Et2O—70 μL) at 0° C. and the resultingsolution was stirred under a nitrogen atmosphere for 15 minutes. Thesolution was concentrated in vacuo and the residue was triturated fromEt2O/n-pentane to give the title compound as a white solid (27 mg).

IR (nujol): 3410 (NH⁺), 1660 (C═O) cm⁻¹.

NMR (d₆-DMSO): δ (ppm) 9.0-8.8 (bm, 2H); 7.95 (bs, 1H); 7.59 (bs, 2H);7.20 (dd, 1H); 6.94 (dd, 1H); 6.84 (m 1H); 4.70 (bd, 2H); 4.63 (d, 1H);4.33 (d, 1H); 4.20 (dd, 1H); 3.51 (m, 1H); 3.37 (bm, 3H); 2.93 (s, 3H);2.75 (m, 1H); 2.35 (s, 3H); 2.16 (m, 1H); 2.11 (m, 1H); 1.73 (m, 1H);1.54 (m, 1H).

MS (ES/+): m/z=538 [MH—HCl]⁺.

EXAMPLE 8

4-(S)—(N-2-Fluoroethyl-N-methylamino)-2-(R)-(4-fluoro-2-methyl-phenyl)-piperidine-1-carboxylicacid, (3,5-bis-trifluoromethyl-benzyl)-methylamide hydrochloride

Formaldehyde (37% in water—43 μL), 10% palladium over charcoal (10 mg)and 1 drop of acetic acid were added to a solution of example 7b (28 mg)in MeOH (1.5 mL). The mixture was stirred at r.t. under a hydrogenatmosphere for 1 hour, then it was filtered though celite andconcentrated in vacuo. The residue was purified by flash chromatography(AcOEt/MeOH 9:1) to give the desired4-(S)—(N-2-fluoroethyl-N-methylamino)-2-(R)-(4-fluoro-2-methyl-phenyl)-piperidine-1-carboxylicacid (3,5-bis-trifluoromethyl-benzyl)-methylamide (13 mg) as yellow gum.This material was dissolved in dry Et2O (2 mL), treated withhydrochloric acid (1M in Et2O—0.5 mL) and the resulting solution wasstirred under a nitrogen atmosphere for 15 minutes. The solution wasconcentrated in vacuo and the residue was triturated from Et2O/n-pentaneto give the title compound as a white solid (11.6 mg).

M.p.: 80-81° C. (dec)

T.l.c.: AcOEt/MeOH 8:2, Rf=0.37 (free base).

IR (nujol): 3387 (NH⁺), 1653 (C═O) cm⁻¹.

NMR (d₆-DMSO): δ (ppm) 10.04 (bm, 1H); 7.96 (s, 1H); 7.6 (s, 2H); 7.28(dd, 1H); 6.94 (dd, 1H); 6.83 (dt 1H); 4.84 (bd, 2H); 4.64 (d, 1H); 4.37(d, 1H); 4.22 (bdd, 1H); 3.6 (bm, 2H); 3.54 (bd, 1H); 3.43 (m, 1H); 2.93(s, 3H); 2.78 (m, 4H); 2.37 (s, 3H); 2.15-2.0 (m, 2H); 1.94 (dt, 1H);1.65 (dq, 1H).

MS (ES/+): m/z=552 [MH—HCl]⁺.

EXAMPLE 92-(R)-(4-Fluoro-2-methyl-phenyl)-4-(R)-(2-methoxyethylamino)-piperidine-1-carboxylicacid [1-(R)-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-methylamidehydrochloride (9a) and2-(R)-(4-Fluoro-2-methyl-phenyl)-4-(S)-(2-methoxyethylamino)-piperidine-1-carboxylicacid [1-(R)-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-methylamidehydrochloride (9b)

A solution of intermediate 4a (100 mg), 2-methoxyethylamine (17 μL) andsodium triacetoxyborohydride (65 mg) in dry 1,2-dichloroethane (5 mL)was stirred at 23° C. for 2 hours under a nitrogen atmosphere. Thesolution was washed with a 5% sodium hydrogen carbonate solution (10 mL)and brine (10 mL). The organic layer was dried and concentrated in vacuoto a residue which was purified by flash chromatography (AcOEt/MeOH 8:2)to give two fractions:

-   1. diastereoisomer 1 (C-2 and C-4 anti configuration—40 mg)-   2. diastereoisomer 2 (C-2 and C-4 syn configuration—20 mg)

EXAMPLE 9a

A solution of diastereoisomer 1 (40 mg) in dry Et2O (3 mL) was treatedwith hydrochloric acid (1M in Et2O—0.5 mL) and the resulting solutionwas stirred at 0 C° for 5 minutes. The solution was concentrated invacuo and the residue was triturated with n-pentane (2 mL) to give thetitle compound as a white solid (40 mg).

IR (nujol): 3396 (NH₂ ⁺), 1640 (C═O) cm⁻¹.

NMR (d₆-DMSO): δ (ppm) 8.67-8.62 (bs, 2H); 7.99 (s, 1H); 7.76 (s, 2H);7.34 (dd, 1H); 6.99 (dd, 1H); 6.91 (m, 1H); 5.12 (m, 1H); 5.09 (m, 1H);3.6-3.4 (m, 4H); 3.16 (m, 3H); 2.25-1.60 (m, 4H); 3.3 (m, 3H); 2.59 (s,3H); 2.23 (s, 3H); 1.55 (d, 3H);

MS (ES/+): m/z=564 [M-Cl]⁺.

EXAMPLE 9b

A solution of diastereoisomer 2 (20 mg) in dry Et2O (3 mL) was treatedwith hydrochloric acid (1M in Et2O—0.5 mL). The resulting solution wasstirred at 23 C° for 30 minutes, then it was concentrated in vacuo. Theresidue was triturated with n-pentane (2 mL) to give the title compoundas a white solid (20 mg).

IR (nujol): 3421 (NH₂ ⁺), 1656-1650 (C═O) cm⁻¹.

NMR (d₆-DMSO): δ (ppm) 8.64 (bs, 2H); 7.99 (s, 1H); 7.67 (s, 2H); 7.14(dd, 1H); 6.94 (dd, 1H); 6.83 (m, 1H); 5.28 (q, 1H); 4.17 (dd, 1H); 3.55(t, 2H); 3.42 (m, 1H); 3.13 (m, 2H); 2.8-2.7 (m, 2H); 2.2-1.5 (m, 4H);3.3 (m, 3H); 2.73 (s, 3H); 2.34 (s, 3H); 1.45 (d, 3H);

MS (ES/+): m/z=564 [M-Cl]⁺.

EXAMPLE 102-(R)-(4-Fluoro-2-methyl-phenyl)-4-(R)-methylamino-piperidine-1-carboxylicacid [1-(R)-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-methylamidehydrochloride (10a) and2-(R)-(4-Fluoro-2-methyl-phenyl)-4-(S)-methylamino-piperidine-1-carboxylicacid [1-(R)-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-methylamidehydrochloride (10b)

Intermediate 4a (120 mg), methylamine (1M solution in THF—2.5 mL) andsodium triacetoxyborohydride (65 mg) in dry 1,2-dichloroethane (5 mL)was stirred at 23° C. for 2 hours under a nitrogen atmosphere. Thesolution was washed with a 5% sodium hydrogen carbonate solution (10 mL)and brine (10 mL). The organic layer was dried and concentrated in vacuoto a residue which was purified by flash chromatography (AcOEt/MeOH75:25) to give two fractions:

-   1. diastereoisomer 1 (40 mg—T.l.c. AcOEt/MeOH 7:3 Rf=0.3)-   2. diastereoisomer 2 (20 mg)—T.l.c. AcOEt/MeOH 7:3 Rf=0.21)

EXAMPLE 10a

A solution of diastereoisomer 1 (40 mg) in dry Et2O (3 mL) was treatedwith hydrochloric acid (1M in Et2O—0.5 mL) and the resulting solutionwas stirred at 0 C° for 5 minutes. The solution was concentrated invacuo and the residue was triturated with n-pentane (2 mL) to give thetitle compound as a white solid (40 mg).

IR (nujol): 3398 (NH₂ ⁺), 1627 (C═O) cm⁻.

NMR (d₆-DMSO): δ (ppm) 8.60 (bs, 2H); 7.99 (s, 1H); 7.75 (s, 2H); 7.32(dd, 1H); 6.99 (dd, 1H); 6.90 (m, 1H); 5.13 (q, 1H); 5.016 (t, 1H); 3.42(m, 2H); 3.14 (m, 1H); 2.61 (s, 3H); 2.57 (s, 3H); 2.24 (s, 3H); 2.12(m, 2H); 1.95 (m, 1H); 1.62 (m, 1H); 1.54 (d, 3H).

MS (ES/+): m/z=520 [MH—HCl]

EXAMPLE 10b

A solution of diastereoisomer B (20 mg) in dry Et2O (3 mL) was treatedwith hydrochloric acid (1M in Et2O—0.5 mL). The solution wasconcentrated in vacuo and the residue was triturated with n-pentane (2mL) to give the title compound as a white solid (20 mg).

IR (nujol): 3398 (NH₂ ⁺), 1658-1650 (C═O) cm⁻¹.

NMR (d₆-DMSO): δ (ppm) 8.60 (bs, 2H); 7.99 (s, 1H); 7.67 (s, 2H); 7.15(dd, 1H); 6.94 (dd, 1H); 6.83 (m, 1H); 5.30 (q, 1H); 4.18 (dd, 1H); 3.42(m, 1H); 3.26 (m, 1H); 1H); 2.76 (t, 1H); 2.73 (s, 3H); 2.55 (s, 3H);2.35 (s, 3H); 2.10-2.00 (m, 1H); 1.68 (m, 1H); 1.53 (m, 1H) 1.45 (d,3H);

MS (ES/+): m/z=520 [MH—HCl]⁺.

EXAMPLE 112-(4-Fluoro-2-methyl-phenyl)-4methylamino-piperidine-1-carboxylic acid(3,5-bis-trifluoromethyl-benzyl)-methylamide (11a—diastereoisomer A) and2-(4-Fluoro-2-methyl-phenyl)-4-methylamino-piperidine-1-carboxylic acid(3,5-bis-trifluoromethyl-benzyl)-methylamide (11b—diastereoisomer B)

A solution of intermediate 3 (150 mg), methylamine (2M in THF—300 μL)and sodium triacetoxyborohydride (100 mg) in dry THF (6 mL) was stirredat r. t. under a nitrogen atmosphere. After 5 hours further methylamine(2M in THF—300 μL) and sodium triacetoxyborohydride (35 mg) were added.After 3 hours the crude solution was quenched with a 5% sodium hydrogencarbonate solution (5 mL) and taken up with AcOEt (5 mL). The aqueousphase was extracted with AcOEt (3×15 mL) and the combined organic phaseswere washed with brine (5 mL). The organic layer was dried andconcentrated in vacuo to a residue which was purified by flashchromatography (AcOEt/MeOH 85:15) to give2-(4-fluoro-2-methyl-phenyl)-4-methylamino-piperidine-1-carboxylic acid(3,5-bis-trifluoromethyl-benzyl)-methylamide in two fractions:

-   1. example 11a (100 mg);-   2. example 11b (13 mg).

EXAMPLE 11a

NMR (d₆-DMSO): δ (ppm) 7.94 (bs, 1H); 7.65 (bs, 2H); 7.24 (dd, 1H); 6.89(dd, 1H); 6.79 (dt, 1H); 4.64 (dd, 1H); 4.57 (d, 1H); 4.37 (d, 1H); 3.19(m, 1H); 3.07 (m, 1H); 2.86 (s, 3H); 2.75 (m, 1H); 2.28 (s, 3H); 2.26(s, 3H); 1.84 (m, 3H); 1.7-1.5 (m, 1H).

MS (ES/+): m/z=506 [MH]⁺.

EXAMPLE 11b

NMR (d₆-DMSO): δ (ppm) 7.93 (bs, 1H); 7.58 (bs, 2H); 7.19 (dd, 1H); 6.89(dd, 1H); 6.77 (dt, 1H); 4.62 (d, 1H); 4.33 (d, 1H); 4.13 (dd, 1H); 3.42(m, 1H); 2.9 (s, 3H); 2.69 (m, 1H); 2.55 (bm, 1H); 2.33 (s, 3H); 2.29(s, 3H); 1.96 (m, 1H); 1.89 (m, 1H); 1.39 (m, 1H); 1.16 (m, 1H).

MS (ES/+): m/z=506 [MH]⁺.

EXAMPLE 122-(4-Fluoro-2-methyl-phenyl)-4-methylamino-piperidine-1-carboxylic acid(3,5-bis-trifluoromethyl-benzyl)-methylamide hydrochloride(diastereoisomer A)

A solution of example 11a (100 mg) in dry Et2O (3 mL) was treated withhydrochloric acid (1M in Et2O—220 μL) at 0° C. The resulting solutionwas stirred under a nitrogen atmosphere for 15 minutes, then it wasconcentrated in vacuo. The residue was triturated with Et2O/n-pentane togive the title compound (81 mg) as a white solid.

NMR (d₆-DMSO): δ (ppm) 8.66 (bm, 2H); 7.94 (bs, 1H); 7.65 (bs, 2H); 7.24(dd, 1H); 6.89 (dd, 1H); 6.79 (dt, 1H); 4.64 (dd, 1H); 4.57 (d, 1H);4.37 (d, 1H); 3.19 (m, 1H); 3.07 (m, 1H); 2.86 (s, 3H); 2.75 (m, 1H);2.28 (s, 3H); 2.26 (s, 3H); 1.84 (m, 3H); 1.7-1.5 (m, 1H).

MS (ES/+): m/z=506 [MH]⁺, 370.

EXAMPLE 132-(4-Fluoro-2-methyl-phenyl)-4-methylamino-piperidine-1-carboxylic acid(3.5-bis-trifluoromethyl-benzyl)-methylamide hydrochloride(diastereoisomer B)

A solution of example 11b (13 mg) in dry Et2O (2 mL) was treated withhydrochloric acid (1M in Et2O—30 μL) at 0° C. and the resulting solutionwas stirred under a nitrogen atmosphere for 15 minutes. The solution wasconcentrated in vacuo and the residue was triturated with Et2O/n-pentaneto give the title compound (10 mg) as a white solid.

NMR (d₆-DMSO): δ (ppm) 8.65 (bm, 2H); 7.94 (bs, 1H); 7.58 (bs, 2H); 7.19(dd, 1H); 6.93 (dd, 1H); 6.82 (dt 1H); 4.62 (d, 1H); 4.33 (d, 1H); 4.18(dd, 1H); 3.49 (m, 1H); 3.25 (bm, 1H); 2.92 (s, 3H); 2.74 (m, 1H); 2.55(s, 3H); 2.35 (s, 3H); 2.12-2.06(m, 2H); 1.68 (m, 1H); 1.48 (q, 1H).

MS (ES/+): m/z=506 [MH]⁺, 370.

EXAMPLE 14 4-Amino-2-(4-fluoro-2-methyl-phenyl)-piperidine-1-carboxylicacid (3,5-bis-trifluoromethyl-benzyl)-methylamide hydrochloride(14a—diastereoisomer A) and4-Amino-2-(4-fluoro-2-methyl-phenyl)-piperidine-1-carboxylic acid(3,5-bis-trifluoromethyl-benzyl)-methylamide hydrochloride(14b—diastereoisomer B)

Methanesulphonyl chloride (20 μL) was added to a solution of2-(4-fluoro-2-methyl-phenyl)-4-hydroxy-piperidine-1-carboxylic acid(3,5-bis-trifluoromethyl-benzyl)-methylamide (intermediate 11a and11b—mixture of syn and anti diastereoisomers—85 mg) and TEA (50 μL) indry THF (5 mL) previously cooled to 0° C. under a nitrogen atmosphere.After 1.5 hours, the solution was quenched with brine (4 mL) andextracted with AcOEt (3×5 mL). The organic layer was dried andconcentrated in vacuo to a residue which was purified by flashchromatography (CH/AcOEt 7:3) to give methanesulfonic acid,1-[(3,5-bis-trifluoromethyl-benzyl)-methyl-carbamoyl]-2-(4-fluoro-2-methyl-phenyl)-piperidin-4-ylester in two fractions:

-   1. diastereoisomer 1 (11 mg);-   2. diastereoisomer 2 (76 mg).

EXAMPLE 14a Diastereoisomer A

A solution of diastereoisomer 2 (11 mg) and sodium azide (2 mg) in dryDMF (2 mL) was stirred at 80° C. for 4 hours under a nitrogenatmosphere. The crude solution was diluted with AcOEt (5 mL) and washedwith cold brine (3×5 mL). The organic layer was dried and concentratedin vacuo to give the crude4-azido-2-(4-fluoro-2-methyl-phenyl)-piperidine-1-carboxylic acid(3,5-bis-trifluoromethyl-benzyl)-methylamide as a semisolid whiteresidue (20 mg) which was treated with triphenylphosphine (10 mg) in dryTHF (3 mL) was stirred at r. t. for 48 hours under a nitrogenatmosphere. Then water (3 μL) was added and the mixture was stirred forfurther 48 hours. The crude solution was taken up with AcOEt (5 mL) andwashed with brine (5 mL). The organic layer was dried and concentratedin vacuo to give the crude4-amino-2-(4-fluoro-2-methyl-phenyl)-piperidine-1-carboxylic acid(3,5-bis-trifluoromethyl-benzyl)-methylamide. This residue was dissolvedin dry Et2O (2 mL), treated with hydrochloric acid (1M in Et2O—100 μL)at 0° C. and the resulting solution was stirred under a nitrogenatmosphere for 15 minutes. The solution was concentrated in vacuo andthe residue was triturated with Et2O/n-pentane to give the titlecompound (9 mg) as a pale yellow solid.

NMR (d₆-DMSO): δ (ppm) 9.92 (bs, 1H); 7.9-7.7 (b, 3H); 7.58 (s, 2H);7.29 (m, 1H); 6.94 (m, 1H); 6.82 (m, 1H); 4.39 (m, 1H); 4.34 (d, 1H);4.16 (d, 1H); 3.50 (m, 1H); 3.31 (m, 1H); 2.93 (m, 1H); 2.92 (s, 3H);2.33 (s, 3H); 2.05-1.65 (m, 4H).

MS (ES/+): m/z=492 [M-Cl]⁺.

EXAMPLE 14b Diastereoisomer B

A solution of diastereoisomer 1 (75 mg) and sodium azide (13 mg) in dryDMF (5 mL) was stirred at 80° C. for 4 hours under a nitrogenatmosphere. The solution was diluted with AcOEt (5 mL) and washed withcold brine (3×5 mL). The organic layer was dried and concentrated invacuo to give the crude4-azido-2-(4-fluoro-2-methyl-phenyl)-piperidine-1-carboxylic acid(3,5-bis-trifluoromethyl-benzyl)-methylamide as a semisolid whiteresidue (80 mg). This residue (60 mg) treated with—triphenylphosphine(30 mg) in dry THF (6 mL) was stirred at r. t. for 48 hours under anitrogen atmosphere. Then, water (3 μL) was added and the mixture wasstirred for further 48 hours. The crude solution was taken up with AcOEt(5 mL) and washed with brine (5 mL). The organic layer was dried andconcentrated in vacuo to give the crude4-amino-2-(4-fluoro-2-methyl-phenyl)-piperidine-1-carboxylic acid(3,5-bis-trifluoromethyl-benzyl)-methylamide.

This residue was dissolved in dry Et2O (2 mL), treated with hydrochloricacid (1M in Et2O—300 μL) at 0° C. and the resulting solution was stirredunder a nitrogen atmosphere for 15 minutes. The solution wasconcentrated in vacuo and the residue was triturated with Et2O/n-pentaneto give the title compound (10 mg) as a white solid.

NMR (d₆-DMSO): δ (ppm) 7.98 (s, 1H); 7.9-7.7 (b, 3H); 7.74 (s, 2H); 7.31(m, 1H); 6.98 (m, 1H); 6.90 (m, 1H); 4.93 (t, 1H); 4.57 (d, 1H); 4.42(d, 1H); 3.56 (m, 1H); 3.30 (m, 1H); 3.13 (m, 1H); 2.83 (s, 3H); 2.26(s, 3H); 2.02-1.62 (m, 4H).

MS (ES/+): m/z=492 [M-Cl]⁺, 475 [M−HCl—NH₃]⁺.

EXAMPLE 154-(R)-Cyclobutylamino-2-(R)-(fluoro-2-methyl-phenyl)-piperidine-1-carboxylicacid [1-(R)-(3,5-bis)-trifluoromethyl-phenyl)-ethyl]-methylamidehydrochloride (15a) and4-(S)-Cyclobutylamino-2-(R)-(4-fluoro-2-methyl-phenyl)-piperidine-1-carboxylicacid [1-(R)-(3,5-bis)-trifluoromethyl-phenyl)-ethyl]-methylamidehydrochloride (15b)

A solution of intermediate 4a (120 mg), cyclobutylamine (20.4 μL) andsodium triacetoxyborohydride (75.5 mg) in dry 1,2-dichloroethane (10 mL)was stirred at 23° C. for 4 hours under a nitrogen atmosphere. Thesolution was washed with a 5% sodium hydrogen carbonate solution (10 mL)and brine (10 mL). The organic layer was dried and concentrated in vacuoto a residue that was purified by flash chromatography (AcOEt/MeOH 9:1)to give:

-   1. diastereoisomer 1 (55.9 mg—T.l.c.: AcOEt/MeOH 8:2 Rf=0.44),-   2. a mixture of the two diastereoisomer (33.3 mg)-   3. diastereoisomer 2 (22.9 mg—T.l.c.: AcOEt/MeOH 8:2 Rf=0.3).

EXAMPLE 15a

A solution of diastereoisomer 1 (53.5 mg) in dry Et2O (10 mL) wastreated with hydrochloric acid (1M in Et2O—2 mL) and the resultingsolution was stirred at 23° C. for 30 minutes. The solution wasconcentrated in vacuo to give the title compound as a white solid (54mg).

M.p.: 68-70° C. (dec).

IR (nujol): 3400, 3000-2400 (NH₂ ⁺), 1637 (C═O) cm⁻¹.

NMR (d₆-DMSO): δ (ppm) 8.79 (bs, 2H); 7.99 (s, 1H); 7.74 (s, 2H); 7.28(dd, 1H); 6.97 (dd, 1H); 6.89 (dd, 1H); 5.13 (q, 1H); 4.98 (bt, 1H);3.83 (m, 1H); 3.45-3.35 (m, 2H); 3.11 (m, 1H); 2.62 (s, 3H); 2.25 (s,3H); 2.18 (2m, 4H); 1.92-1.76 (2m, 2H); 1.61 (m, 2H); 1.53 (d, 3H); 1.24(m, 1H); 0.84 (m, 1H).

MS (ES/+): m/z=560 [MH—HCl]⁺.

EXAMPLE 15b

A solution of diastereoisomer 2 (21.2 mg) in dry Et2O (5 mL) was treatedwith hydrochloric acid (1M in Et2O—2 mL). The resulting mixture wasstirred at 23° C. for 15 minutes, then filtered to give the titlecompound as a whitish solid (22 mg).

M.p.: 211-213° C. (dec).

IR (nujol): 3400-2500 (NH₂ ⁺), 1664 (C═O) cm⁻¹.

NMR (d₆-DMSO): δ (ppm) 9.07 (bs, 2H); 7.98 (bs, 1H); 7.65 (bs, 2H); 7.13(m, 1H); 6.93 (m, 1H); 6.81 (m, 1H); 5.27 (m, 1H); 4.17 (m, 1H); 3.80(bm, 1H); 3.4-3.3 (m, 2H); 2.77 (m, 1H); 2.72 (m, 3H); 2.33 (s, 3H);2.17 (m, 4H); 2.07-1.99 (m, 2H); 1.8-1.4 (m, 2H); 1.44 (d, 3H); 1.24 (m,1H); 0.84 (m, 1H).

MS (ES/+): m/z=560

EXAMPLE 164-(R)-Cyclopropylamino-2-(R)-(4-fluoro-2-methyl-phenyl)-piperidine-1-carboxylicacid [1-(R)-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-methylamidehydrochloride (16a) and4-(S)-Cyclopropylamino-2-(R)-(4-fluoro-2-methyl-phenyl)-piperidine-1-carboxylicacid [1-(R)-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-methylamidehydrochloride (16b)

A solution of intermediate 4a (120 mg), cyclopropylamine (16.6 μL) andsodium triacetoxyborohydride (78.2 mg) in dry 1,2-dichloroethane (5 mL)was stirred at 23° C. for 2 hours under a nitrogen atmosphere. Thesolution was washed with a 5% sodium hydrogen carbonate solution (10 mL)and brine (10 mL). The organic layer was dried and concentrated in vacuoto a residue that was purified by flash chromatography (AcOEt/MeOH85:15) to give three fractions:

-   1. diastereoisomer 1 (59.5 mg—T.l.c.: AcOEt/MeOH 7:3 Rf=0.40),-   2. a mixture of the two diastereoisomer (20.0 mg)-   3. diastereoisomer 2 (32.0 mg—T.l.c.: AcOEt/MeOH 7:3 Rf=0.37).

EXAMPLE 16a

A solution of diastereoisomer 1 (59.5 mg) in dry Et2O (5 mL) was treatedwith hydrochloric acid (1M in Et2O—1 mL) and the resulting solution wasstirred at 23° C. for 30 minutes. The solution was concentrated in vacuoto give the title compound as a white solid (59.5 mg).

IR (nujol): 3404, (NH₂ ⁺), 1639 (C═O) cm⁻¹.

NMR (d₆-DMSO): δ (ppm) 8.86 (bs, 2H); 8.77 (bs, 1H); 8.00 (s, 1H); 7.76(s, 2H); 7.34 (dd, 1H); 6.99 (dd, 1H); 6.92 (dt, 1H); 5.15 (q, 1H); 5.04(bt, 1H); 3.66 (bm, 1H); 3.42 (bm, 1H); 3.14 (dt, 1H); 2.74 (bm, 1H);2.63 (s, 3H); 2.25 (s, 3H); 2.19 (bm, 2H); 2.02 (bm, 1H); 1.68 (m, 1H);1.55 (d, 3H); 0.84 (bm, 2H); 0.79 (bm, 2H).

MS (ES/+): m/z=546 [MH—HCl]⁺.

EXAMPLE 16b

A solution of diastereoisomer 2 (32.0 mg) in dry Et2O (5 mL) was treatedwith hydrochloric acid (1M in Et2O—1 mL). The resulting mixture wasstirred at 23° C. for 15 minutes, then filtered and treated with furtherdiethyl ether to give the title compound as a whitish solid (20 mg).

IR (nujol): 3383 (NH₂ ⁺), 1650 (C═O) cm⁻¹.

NMR (d₆-DMSO): δ (ppm) 9.00 (sa, 2H); 7.99 (s, 1H); 7.67 (s, 2H); 7.15(dd, 1H); 6.94 (dd, 1H); 6.83 (m, 1H); 5.29 (q, 1H); 4.21 (dd, 1H); 2.73(s, 3H); 2.45 (m, 2H); 2.35 (s, 3H); 2.9-2.2 (m, 2H); 1.8-0.7 (m, 8H);1.45 (d, 3H).

MS (ES/+): m/z=546 [MH—HCl]⁺.

EXAMPLE 172-(R)-(4-Fluoro-2-methyl-phenyl)-4-(R,S)-[methyl-(1-methyl-piperidin-4-yl)-amino]-piperidine-1-carboxylicacid [1-(R)-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-methylamidehydrochloride

A solution of intermediate 4a (120 mg),1-methyl-4-(methylamino)-piperidine (34.6 μL) and sodiumtriacetoxyborohydride (75.5 mg) in dry 1,2-dichloroethane (2.5 mL) wasstirred at 23° C. overnight under a nitrogen atmosphere. The solutionwas washed with a 5% sodium hydrogen carbonate solution (10 mL) andbrine (10 mL). The organic layer was dried and concentrated in vacuo toa residue which was purified by flash chromatography (AcOEt/MeOH from10:0 to 1:1) to give the2-(4-fluoro-2-methyl-phenyl)-4-[methyl-(1-methyl-piperidin-4-yl)-amino]-piperidine-1-carboxylicacid [1-(R)-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-methylamide (43 mgas a mixture of diastereoisomer A and diastereoisomer B) which wasdissolved in dry Et2O (5 mL) and treated with hydrochloric acid (1M inEt2O—1 mL). The resulting mixture was stirred at 23° C. for 30 minutes,then it was concentrated in vacuo. The residue was triturated with Et2Oto give the title compound (25 mg) as a white solid and as a mixture ofanti/syn 60:40.

NMR (d₆-DMSO): δ (ppm) 10.40 and 9.50 (2bs, 2H); 7.90 (d, 1H); 7.73 and7.67 (2s, 2H); 7.30 and 7.22 (2bt, 1H); 6.94-6.75 (2m, 2H); 5.31 and5.11 (2q, 1H); 5.00 and 4.24 (2bd, 1H); 2.36 and 2.27 (2s, 3H); 1.53 and1.46 (2d, 3H); 2.74-2.61 (6s, 9H); 3.40-1.75 (14m, 16H).

MS (ES/+): m/z=617 [MH—HCl]⁺.

EXAMPLE 184-Benzylamino-2-(4-fluoro-2-methyl-phenyl)-piperidine-1-carboxylic acid(3,5-bis-trifluoromethyl-benzyl)-methylamide (18a—diastereoisomer A) and4-Benzylamino-2-(4-fluoro-2-methyl-phenyl)-piperidine-1-carboxylic acid(3,5-bis-trifluoromethyl-benzyl)-methylamide (18 b—diastereoisomer B)

A solution of intermediate 3 (30 mg), benzylamine (7.5 μL), acetic acid(6 μL) and sodium triacetoxyborohydride (22 mg) in dry1,2-dichloroethane (2 mL) was stirred at r.t. under a nitrogenatmosphere. After 0.5 hours further benzylamine (7.5 μL) and sodiumtriacetoxyborohydride (22 mg) were added. After 1.5 hours the crudesolution was quenched with a 1N potassium hydroxide solution (2 mL) andtaken up with AcOEt (5 mL). The aqueous phase was extracted with AcOEt(3×5 mL) and the combined organic phases were washed with brine (5 mL).The organic layer was dried and concentrated in vacuo to a residue whichwas purified by flash chromatography (AcOEt/MeOH 9:1) to give twofractions:

-   1. diastereoisomer A (24 mg—T.l.c.: AcOEt/MeOH 9:1 Rf=0.45),-   2. diastereoisomer B (10 mg—T.l.c.: AcOEt/MeOH 9:1 Rf=0.3).

EXAMPLE 18a (diastereoisomer A)

NMR (d₆-DMSO): δ (ppm) 7.95 (bs, 1H); 7.60 (bs, 2H); 7.20 (m, 6H); 6.90(m, 1H); 6.79 (m, 1H); 4.64 (d, 1H); 4.30 (d, 1H); 4.10 (m, 1H); 3.65(bs, 2H); 3.15 (m, 1H); 2.90 (s, 3H); 2.65 (m, 1H); 2.35 (m, 1H); 2.25(s, 3H); 1.90 (m, 2H); 1.6-1.5 (m, 2H).

MS (ES/+): m/z=582 [MH]⁺, 446.

EXAMPLE 18b Diastereoisomer B

NMR (d₆-DMSO): δ (ppm) 7.93 (bs, 1H); 7.58 (bs, 2H); 7.25 (m, 6H); 6.88(dd, 1H); 6.77 (dt, 1H); 4.62 (d, 1H); 4.32 (d, 1H); 4.09 (dd, 1H); 3.71(s, 2H); 3.40 (m, 1H); 2.90 (s, 3H); 2.65 (m, 1H); 2.59 (m, 1H); 2.31(s, 3H); 1.95(m, 2H); 1.43 (m, 1H); 1.20 (m, 1H).

MS (ES/+): m/z=582 [MH]⁺, 446.

EXAMPLE 194-[(1,3-Dioxolan-2-yl)-methyl]-amino-2-(4-fluoro-2-methyl-phenyl)-piperidine-1-carboxylicacid, (3,5-bis-trifluoromethyl-benzyl)-methylamide

A solution of intermediate 3 (10 mg), 2-(aminomethyl)-1,3-dioxolane(2.09 mg), sodium triacetoxyborohydride (6.45 mg) and acetic acid (1,7μl) in dry 1,2-dichloroethane (400 μl) was stirred at 23° C. for 18hours. The solution was diluted with DCM (1 mL) and washed with a 0.5Nsolution of sodium hydroxide (1 mL). The two phases were separated usinga Whatman filter tube with polypropylene filter and the organic solutionwas then passed through a SCX cartridge (Varian, 100 mg). The cartridgewas washed with MeOH (3 mL) and the product was then released by addinga 0.25M solution of ammonia in MeOH (1 mL) and washing with MeOH (1 mL).The solution was concentrated in vacuo to give the title compound (7 mg)as a mixture of diastereoisomers A and B in ratio 70:30.

Diastereoisomer A:

NMR (CDCl₃): δ (ppm) 7.75 (bs, 1H); 7.53 (s, 2H); 7.25 (dd, 1H);6.85-6.78 (m, 2H); 4.96 (dd, 1H); 4.57 (d, 1H); 4.43 (d, 1H); 5.01 (t,1H); 3.99 (m, 2H); 3.90 (m, 2H); 2.88 (s, 3H); 2.34 (s, 3H); 2.84 (d,2H); 3.48-3.38 and 3.18-3.08 and 2.14-1.50(m, 7H).

MS (ES/+): m/z=577.

Diastereoisomer B:

NMR (CDCl₃): δ (ppm) 7.75 (bs, 1H); 7.67 (bs, 1H); 7.42 (s, 2H); 7.17(dd, 1H); 6.85-6.78 (m, 2H); 4.28 (dd, 1H); 4.65 (d, 1H); 4.37 (d, 1H);4.99 (t, 1H); 3.99 (m, 2H); 3.90 (m, 2H); 2.96 (s, 3H); 2.43 (s, 3H);2.86 (d, 2H); 3.48-3.38 and 3.18-3.08 and 2.14-1.50(m, 7H).

MS (ES/+): m/z=577.

EXAMPLE 204-(R)-N-2-Fluoroethyl-N-methylamino)-2-(R)-(4-fluoro-2-methyl-phenyl)-piperidine-1-carboxylicacid (3,5-bis-trifluoromethyl-benzyl)-methylamide hydrochloride

Formaldehyde (37% in water—208 μL), 10% palladium over charcoal (34 mg)and 2 drops of acetic acid were added to a solution of Example 7a (98mg) in MeOH (5 mL). The mixture was stirred at r.t. under a hydrogenatmosphere for 1 hour, then it was filtered though celite andconcentrated in vacuo. The residue was purified by flash chromatography(AcOEt/MeOH 9:1) to give the4-(R)-(N-2-fluoroethyl-N-methylamino)-2-(R)-(4-fluoro-2-methyl-phenyl)-piperidine-1-carboxylicacid (3,5-bis-trifluoromethyl-benzyl)-methylamide (85 mg—T.l.c.:AcOEt/MeOH 8:2, Rf=0.37). This material was dissolved in dry Et2O (5mL), treated with hydrochloric acid (1M in Et2O—0.5 mL) and theresulting solution was stirred under a nitrogen atmosphere for 15minutes. The solution was concentrated in vacuo and the residue wastriturated from Et2O/n-pentane to give the title compound as a whitesolid (85 mg).

IR (nujol): 3348 (NH⁺), 1628 (C═O) cm⁻¹.

NMR (d₆-DMSO): δ (ppm) 8.9 (bs, 1H); 7.99 (s, 1H); 7.78 (s, 2H); 7.35(dd, 1H); 7.0 (dd, 1H); 6.92 (dt 1H); 5.08 (bt, 1H); 4.73 (d, 2H); 4.58(d, 1H); 4.43 (d, 1H); 3.65 (bm, 1H); 3.42-3.3 (m, 3H); 3.11 (dt, 1H);2.81 (s, 3H); 2.5 (m, 3H); 2.27 (s, 3H); 2.17 (m, 1H); 2.11 (m, 1H);2.06 (m, 1H); 1.69 (m, 1H).

MS (ES/+): m/z=552 [MH—HCl]⁺.

EXAMPLE 214-(R)-(Carbamoylmethyl-amino)-2-(R)-(4-fluoro-2-methyl-phenyl)-piperidine-1-carboxylicacid (3,5-bis-trifluoromethyl-benzyl)-methylamide hydrochloride (21a)and4-(S)-(Carbamoylmethyl-amino)-2-(R)-(4-fluoro-2-methyl-phenyl)-piperidine-1-carboxylicacid (3,5-bis-trifluoromethyl-benzyl)-methylamide hydrochloride (21b)

A solution of intermediate 10 (120 mg), glycinamide hydrochloride (81mg) and TEA (102 μL) in dry 1,2-dichloroethane (2 mL) and acetonitrile(2 mL) was stirred at r.t. for 1 hour under a nitrogen atmosphere. Thensodium triacetoxyborohydride (78 mg) was added and the mixture wasstirred at 23° C. for 18 hours. The solution was washed with a 5% sodiumhydrogen carbonate solution (10 mL) and extracted with DCM (2×10 mL).The combined organic extracts were washed with brine (10 mL), dried andconcentrated in vacuo to a residue, which was purified by flashchromatography (AcOEt/MeOH 8:2) to give two fractions:

-   1. diastereoisomer 1 (47 mg—T.l.c.: AcOEt/MeOH 8:2, Rf=0.22);-   2. diastereoisomer 2 (35 mg—T.l.c.: AcOEt/MeOH 8:2 Rf=0.13).

EXAMPLE 21a

A solution of diastereoisomer 1 (47 mg) in dry Et2O (5 mL) was treatedwith hydrochloric acid (1M in Et2O—0.1 mL). The resulting mixture wasstirred at 0° C. for 15 minutes, then filtered to give the titlecompound as a yellow solid (41.5 mg).

M.p.: 130-1° C.

IR (nujol): 3325 (NH₂ ⁺), 1697 (C═O) cm⁻¹.

NMR (d₆-DMSO): δ (ppm) 8.97 (bs, 1H); 8.92 (bs, 1H); 7.98 (s, 1H); 7.85(s, 1H); 7.78 (s, 2H); 7.62 (s, 1H); 7.34 (td, 1H); 7.0 (dd, 1H); 6.91(td, 1H); 5.1 (t, 1H); 4.57 (d, 1H); 4.41 (d, 1H); 3.74 (bs, 2H); 3.59(bs, 1H); 3.46 (bd, 1H); 3.09 (t, 1H); 2.78 (s, 3H); 2.26 (s, 3H); 2.19(m, 1H); 2.03 (m, 2H); 1.66 (m, 1H).

MS (ES/+): m/z=549 [M+H]⁺.

EXAMPLE 21b

A solution of diastereoisomer 2 (35 mg) in dry Et2O (5 mL) was treatedwith hydrochloric acid (1M in Et2O—0.1 mL). The resulting mixture wasstirred at 0° C. for 15 minutes, then filtered to give the titlecompound as a yellow solid (27 mg).

M.p.: 100-1° C.

IR (nujol): 3300-3100 (NH₂ ⁺), 1695 (C═O) cm⁻¹.

NMR (d₆-DMSO): δ (ppm) 8.97 (bd, 2H); 7.94 (s, 1H); 7.81 (s, 1H); 7.59(s, 3H); 7.18 (t, 1H); 6.94 (d, 1H); 6.83 (t, 1H); 4.64 (d, 1H); 4.33(d, 1H); 4.17 (dd, 1H); 3.71 (bm, 2H); 3.51 (d, 1H); 3.41 (m, 1H); 2.92(s, 3H); 2.72 (t, 1H); 2.34 (s, 3H); 2.11 (d, 1H); 2.05 (d, 1H); 1.77(m, 1H); 1.59 (m, 1H).

MS (ES/+): m/z=549 [M+H]⁺.

EXAMPLE 222-(R)-(4-Fluoro-2-methyl-phenyl)-4-(R)-morpholino-piperidine-1-carboxylicacid (3,5-bis-trifluoromethyl-benzyl)-methylamide (22a)2-(R)-(4-Fluoro-2-methyl-phenyl)-4-(S)-morpholino-piperidine-1-carboxylicacid (3,5-bis-trifluoromethyl-benzyl)-methylamide (22b)

A solution of intermediate 10 (500 mg) and morpholine (230 μL) in dryacetonitrile (5 mL) was stirred at r.t. for 1 hour under a nitrogenatmosphere. Then sodium triacetoxyborohydride (390 mg) was added and themixture was stirred at 23° C. for 18 hours. The solution was washed witha saturated sodium hydrogen carbonate solution and extracted with AcOEt.The organic extract was washed with brine, dried and concentrated invacuo to a residue, which was purified by flash chromatography(AcOEt/MeOH 97:3) to give two fractions:

-   1. example 22a (187 mg);-   2. example 22b (209 mg).

EXAMPLE 22a

NMR (CDCl₃): δ (ppm) 7.77 (bs, 1H); 7.55 (bs, 2H); 7.27 (m, 1H); 6.83(m, 2H);5.06 (dd, 1H); 4.51 (m, 2H); 3.75 (m, 4H); 3.52 (m, 1H); 3.15(m, 1H); 2.88 (s, 3H); 2.6 (m, 1H); 2.55 (m, 4H); 2.34 (s, 3H);2.04-1.88 (2m, 4H).

EXAMPLE 22b

NMR (CDCl₃): δ (ppm) 7.76 (bs, 1H); 7.44 (bs, 2H); 7.18 (dd, 1H); 6.83(m, 2H); 4.67-4.4 (2d, 2H); 4.3 (dd, 1H); 3.71 (m, 4H); 3.48 (m, 1H);2.98 (s, 3H); 2.86 (m, 1H); 2.58 (m, 4H); 2.5 (m, 1H); 2.45 (s, 3H);2.04-1.98 (2m, 4H); 1.67 (dq, 1H); 1.48 (q, 1H).

EXAMPLE 232-(R)-(4-Fluoro-2-methyl-phenyl)-4-(R)-morpholino-piperidine-1-carboxylicacid (3,5-bis-trifluoromethyl-benzyl)-methylamide

A solution of example 22a (175 mg) in dry Et2O (3 mL) previously cooledto 0° C. was treated with hydrochloric acid (1M in Et2O—343 μL). Theresulting mixture was stirred at 0° C. for 30 minutes, then pentane (5mL) was added and the solid was filtered off to give the title compoundas a white solid (102 mg).

NMR (d₆-DMSO): δ (ppm) 10.31 (bd, 1H); 7.99(s, 1H); 7.82(s, 2H); 7.3(dd, 1H); 7.02 (dd, 1H); 6.94 (dd, 1H); 5.25 (s, 1H); 4.59 (d, 1H); 4.42(d, 1H); 3.99 (dd, 2H); 3.73 (d, 1H); 3.59 (dd, 1H); 3.53 (d, 1H); 3.44(d, 1H); 3.08 (dd, 3H); 2.75 (s, 3H); 2.24 (s, 3H); 2.17 (m, 3H); 1.68(dd, 1H).

EXAMPLE 242-(R)-(4-Fluoro-2-methyl-phenyl)-4-(S)-morpholino-piperidine-1-carboxylicacid (3,5-bis-trifluoromethyl-benzyl)-methylamide

A solution of example 22b (202 mg) in dry Et2O (7 mL) and THF (0.5 mL)previously cooled to 0° C. was treated with hydrochloric acid (1M inEt2O—396 μL). The resulting mixture was stirred at 0° C. for 30 minutes,then concentrated in vacuo to give the title compound as a white solid(199 mg).

NMR (d₆-DMSO): δ (ppm) 10.97 (bd, 1H); 7.95 (s, 1H); 7.6 (s, 2H); 7.25(dd, 1H); 6.94 (dd, 1H); 6.93 (dd, 1H); 4.63 (d, 1H); 4.36 (d, 1H); 4.19(d, 1H); 3.94 (dd, 2H); 3.8 (m, 2H); 3.55 (d, 1H); 3.45 (dd, 1H); 3.42(d, 2H); 3.07 (dd, 2H); 2.93 (s, 3H); 2.73 (dd, 1H); 2.37 (s, 3H); 2.21(dd, 2H); 1.91 (dd, 1H); 1.7 (dd, 1H).

EXAMPLE 252-(R)-(4-Fluoro-2-methyl-phenyl)-4-(R)-morpholino-piperidine-1-carboxylicacid 1-[(R)-(3.5-bis-trifluoromethyl-phenyl)-ethyl]-methylamide (25a)2-(R)-(4-Fluoro-2-methyl-phenyl)-4-(S)-morpholino-piperidine-1-carboxylicacid 1-[(R)-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-methylamide (25b)

A solution of intermediate 4a (238 mg) and morpholine (106 μL) in dryacetonitrile (5 mL) was stirred at r.t. for 1 hour under a nitrogenatmosphere. Then sodium triacetoxyborohydride (179 mg) was added and themixture was stirred at 23° C. for 18 hours. The solution was washed witha saturated sodium hydrogen carbonate solution and extracted with AcOEt.The organic extract was washed with brine, dried and concentrated invacuo to a residue, which was purified by HPLC (Column Chiralcel OD 25cm×20 mm, n-hexane/EtOH 97:3, flow 7.5 mL/min, λ=225 nm) to give threefractions:

-   1. example 25b (119 mg);-   2. mixture of example 25a and 25b (30 mg);-   3. example 25a (76 mg).

EXAMPLE 25a

NMR (d₆-DMSO): δ (ppm) 7.97 (s, 1H); 7.71 (s, 2H); 7.26 (dd, 1H); 6.91(dd, 1H); 6.82 (m, 1H); 5.16 (q, 1H); 4.83 (m, 1H); 3.59 (m, 4H); 3.3(m, 1H); 3.15 (m, 1H; 2.61 (s, 3H); 2.41 (m, 4H); 2.4 (m, 1H); 2.24 (s,3H); 1.9-1.65 (m, 4H); 1.49 (d, 3H).

HPLC: column Chiralcel OD 25 cm×4.6 mm; mobile phase: n-hexane/EtOH97:3, flow 1 mL/min, λ=225 nm; retention time 7.54 minutes.

EXAMPLE 25b

NMR (d₆-DMSO): δ (ppm) 7.98 (s, 1H); 7.67 (s, 2H); 7.16 (dd, 1H); 6.9(dd, 1H); 6.74 (m, 1H); 5.32 (q, 1H); 4.12 (dd, 1H); 3.51 (m, 4H); 3.4(m, 1H); 2.7 (m, 4H); 2.44 (m, 4H); 2.4 (m, 1H); 2.33 (s, 3H); 1.9 (m,2H); 1.6 (m, 1H); 1.45 (d, 3H); 1.37 (m, 1H).

HPLC: column Chiralcel OD 25 cm×4.6 mm; mobile phase: n-hexane/EtOH97:3, flow 1 mL/min, λ=225 nm; retention time 6.61 minutes.

EXAMPLE 262-(R)-(4-Fluoro-2-methyl-phenyl)-4-(R)-morpholino-piperidine-1-carboxylicacid 1-[(R)-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-methylamidehydrochloride

A solution of example 25a (62 mg) in dry Et2O (1.5 mL) previously cooledto 0° C. was treated with hydrochloric acid (1M in Et2O—119 μL). Theresulting mixture was stirred at 0° C. for 30 minutes, then pentane (4mL) was added and the solid was filtered off to give the title compoundas a white solid (56 mg).

NMR (d₆-DMSO): δ (ppm) 10.27 (bs, 1H); 8.0 (bs, 1H); 7.78 (bs, 2H); 7.38(dd, 1H); 7.01 (dd, 1H); 6.93 (dt, 1H); 5.25 (t, 1H); 5.07 (q, 1H);3.98-3.74 (2t, 4H); 3.63, 3.5, 3.42 (3m, 4H); 3.13 (m, 3H); 2.56 (s,3H); 2.34 (m, 1H); 2.22 (s, 3H); 2.15 (m, 1H); 1.68 (m, 1H); 1.57 (d,3H).

EXAMPLE 272-(R)-(4-Fluoro-2-methyl-phenyl)-4-(S)-morpholino-piperidine-1-carboxylicacid 1-[(R)-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-methylamidehydrochloride

A solution of example 25b (101 mg) in dry Et2O (2 mL) previously cooledto 0° C. was treated with hydrochloric acid (1M in Et2O—190 μL). Theresulting mixture was stirred at 0° C. for 1 hour, then pentane (5 mL)was added and the solid was filtered off to give the title compound as awhite solid (93 mg).

NMR (d₆-DMSO): δ (ppm) 10.62 (bs, 1H); 7.99 (bs, 1H); 7.68 (bs, 1H);7.21 (dd, 1H); 6.95 (dd, 1H); 6.83 (dt, 1H); 5.31 (q, 1H); 4.18 (dd,1H); 3.95 (t, 2H); 3.76 (t, 2H); 3.45 (m, 4H); 3.08 (m, 2H); 2.77 (t,1H); 2.74 (s, 3H); 2.36 (s, 3H); 2.18 (m, 2H); 1.87 (m, 1H); 1.74 (q,1H); 1.46 (d, 3H).

EXAMPLE 282-(R)-(4-Fluoro-2-methyl-phenyl)-4-(R)-morpholino-piperidine-1-carboxylicacid 1-[(S)-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-methylamide (28a)2-(R)-(4-Fluoro-2-methyl-phenyl)-4-(S)-morpholino-piperidine-1-carboxylicacid 1-[(S)-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-methylamide (28b)

A solution of intermediate 5b (290 mg) and morpholine (130 μL) in dryacetonitrile (5 mL) was stirred at r.t. for 1 hour under a nitrogenatmosphere. Then sodium triacetoxyborohydride (217 mg) was added and themixture was stirred at 23° C. for 18 hours. The solution was washed witha saturated sodium hydrogen carbonate solution and extracted with AcOEt.The organic extract was washed with brine, dried and concentrated invacuo to a residue, which was purified by flash chromatography(AcOEt/MeOH 97:3) to give:

-   1. example 28a (87 mg);-   2. example 28b (100 mg).

EXAMPLE 28a

NMR (CDCl₃): δ (ppm) 7.75 (bs, 1H); 7.6 (bs, 2H); 7.24 (dd, 1H); 6.83(m, 2H); 5.54 (q, 1H); 5.03 (dd, 1H); 3.76 (m, 4H); 3.44 (m, 1H); 3.09(m, 1H); 2.72 (s, 3H); 2.59 (m, 1H); 2.56 (m, 4H); 2.35(s, 3H); 2.05 (m,2H); 1.85 (m, 2H); 1.54 (d, 3H).

EXAMPLE 28b

NMR (CDCl₃): δ (ppm) 7.73 (bs, 1H); 7.44 (bs, 2H); 7.14 (dd, 1H); 6.84(dd, 1H); 6.79 (dt, 1H); 5.62 (q, 1H); 4.3 (dd, 1H); 3.71 (m, 4H); 3.44(m, 1H); 2.83 (m, 1H); 2.82 (s, 3H); 2.57 (m, 4H); 2.45 (m+s, 4H); 2.01(m, 2H); 1.64 (m, 1H); 1.52 (d, 3H); 1.45 (q, 1H).

EXAMPLE 292-(R)-(4-Fluoro-2-methyl-phenyl)-4-(R)-morpholino-piperidine-1-carboxylicacid 1-[(S)-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-methylamidehydrochloride

A solution of example 28a (80 mg) in dry Et2O (1.5 mL) previously cooledto 0° C. was treated with hydrochloric acid (1M in Et2O—150 μL). Theresulting mixture was stirred at 0° C. for 1 hour, then it was filteredto give the title compound as a pale yellow solid (71 mg).

NMR (d₆-DMSO): δ (ppm) 10.17 (bs, 1H); 7.99 (s, 1H); 7.84 (s, 2H); 7.41(dd, 1H); 7.04 (dd, 1H); 6.94 (dt, 1H); 5.29 (q, 1H); 5.25 (m, 1H); 4.01(m, 2H); 3.76 (m, 2H); 3.73 (m, 1H); 3.5 (m, 2H); 3.48 (m, 1H); 3.13 (m,2H); 2.97 (t, 3H); 2.63 (s, 1H); 2.34 (m, 2H); 2.23 (s, 3H); 2.16 (m,1H); 1.66 (m, 1H); 1.54 (d, 3H).

EXAMPLE 302-(R)-(4-Fluoro-2-methyl-phenyl)-4-(S)-morpholino-piperidine-1-carboxylicacid 1-[(S)-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-methylamidehydrochloride

A solution of example 28b (90 mg) in dry Et2O (1.5 ML) previously cooledto 0° C. was treated with hydrochloric acid (1M in Et2O—172 μL). Theresulting mixture was stirred at 0° C. for 1 hour, then pentane (5 mL)was added and the mixture was filtered to give the title compound as awhite solid (89 mg).

NMR (d₆-DMSO): δ (ppm) 10.55 (bs, 1H); 7.94 (s, 1H); 7.54 (s, 2H); 7.21(dd, 1H); 6.93 (dd, 1H); 6.8 (dt, 1H); 5.33 (q, 1H); 4.18 (dd, 1H);3.95-3.75 (2m, 4H); 3.54 (m, 1H); 3.47 (m, 1H); 3.43-3.07 (2m, 4H); 2.84(s, 3H); 2.68 (t, 1H); 2.36 (s, 3H); 2.2 (m, 2H); 1.88 (dq, 1H); 1.64(q, 1H); 1.5 (d, 3H).

EXAMPLE 314-Cyclopropylamino-1-(4-fluoro-2-methyl-phenyl)-piperidine-2-carboxylicacid (3,5-dichloro-benzyl)-methylamide (31a—diastereoisomer A) and4-Cyclopropylamino-1-(4-fluoro-2-methyl-phenyl)-piperidine-2-carboxylicacid (3,5-dichloro-benzyl)-methylamide (31b—diastereoisomer B)

Cyclopropylamine (0.012 mL) and sodium triacetoxyborohydride (38.1 mg)were added to a solution of intermediate 5 (50 mg) in anhydrousacetonitrile (3 mL) under a Nitrogen atmosphere. The solution wasstirred at r.t. for 2 hours, then further cyclopropylamine (0.006 mL)and sodium triacetoxyborohydride (25.4 mg) were added. The mixture wasstirred at 23° C. for 2 days. The solution was diluted with AcOEt (15mL) and washed with a 5% sodium hydrogen carbonate solution (15 mL) andbrine (10 mL). The organic layer was dried and concentrated in vacuo toa residue which was purified by flash chromatography (AcOEt/MeOH 85:15)to give two fractions:

-   1. example 31a (8.5 mg) as colourless oil-   2. example 31b (10.1 mg) as colourless oil.

EXAMPLE 31a

T.l.c.:AcOEt/MeOH 85:15, Rf=0.23.

NMR (d₆-DMSO): δ (ppm) 7.36 (bs, 1H); 7.12 (dd, 1H); 6.95 (bs, 2H); 6.89(bd, 1H); 6.82 (bt, 1H); 4.48 (d, 1H); 4.32 (bm, 1H); 4.31 (bm, 1H);3.48 (bm, 1H); 3.1 (bm, 1H); 2.83 (m, 3H); 2.78 (bm, 1H); 2.24 (s, 3H);2.12 (m, 1H); 1.94 (m, 2H); 1.77 (m, 1H); 1.53 (m, 1H); 0.4 (m, 2H);0.26 (m, 2H).

MS (ES/+) m/z=464 [M+H]⁺.

EXAMPLE 31b

T.l.c.:AcOEt/MeOH 85:15, Rf=0.18.

NMR (d₆-DMSO): δ (ppm) 7.33 (bs, 1H); 7.11 (bm, 1H); 6.91 (bd, 2H); 6.85(bs, 1H); 6.82 (bm, 1H); 4.4 (bm, 1H); 4.2 (bm, 1H); 4.15 (bd, 1H); 3.03(bm, 1H); 2.96 (bs, 3H); 2.75 (bt, 1H); 2.5 (bm, 1H); 2.28 (bs, 3H);2.11 (bm, 2H); 1.91 (bm, 1H); 1.53 (bq, 1H); 1.47 (bq, 1H); 0.39 (m,2H); 0.23 (m, 2H).

MS (ES/+) m/z=464 [M+H]⁺.

EXAMPLE 324-Cyclopropylamino-1-(4-fluoro-2-methyl-phenyl)-piperidine-2-carboxylicacid (3,5-dichloro-benzyl)-methylamide hydrochloride (diastereoisomer A)

A solution of example 31a (8 mg) in dry Et2O (1 mL) was treated withhydrochloric acid (1M in Et2O—0.019 mL) at 0° C. under a Nitrogenatmosphere. The resulting solution was stirred at 0° C. for 30 minutes,then it was concentrated in vacuo and the residue was triturated withpentane (2×3 mL) to give the title compound as a white solid (6.6 mg).

NMR (d₆-DMSO—70° C.): δ (ppm) 8.93 (bs, 2H); 7.42 (s, 1H); 7.2-6.8 (bm,5H); 4.7-3.4 (m, 5H); 3.0-2.6 (m, 5H); 2.3-2.0 (m, 6H); 1.76 (m, 1H);1.0-0.8 (m, 4H).

MS (ES/+) m/z=464 [M+H—HCl]⁺.

EXAMPLE 334-Cyclopropylamino-1-(4-fluoro-2-methyl-phenyl)-piperidine-2-carboxylicacid (3,5-dichloro-benzyl)-methylamide hydrochloride (diastereoisomer B)

A solution of example 31b (9 mg) in dry Et2O (1 mL) was treated withhydrochloric acid (1M in Et2O—0.021 mL) at 0° C. under a Nitrogenatmosphere. The resulting solution was stirred at 0° C. for 30 minutes,then it was concentrated in vacuo and the residue was triturated withpentane (2×3 mL) to give the title compound as a white solid (9.3 mg).

NMR (d₆-DMSO—70° C.): δ (ppm) 9.0 (bs, 2H); 7.36 (s, 1H); 7.15 (bt, 1H);6.95 (dd, 1H); 6.85 (m, 1H); 6.83 (s, 2H); 4.3 (bd, 1H); 4.8-4.0 (bm,2H); 3.45 (bm, 1H); 3.0 (m, 1H); 2.8-2.5 (m, 2H); 3.04 (s, 3H); 2.31 (s,3H); 2.3 (bm, 1H); 2.13 (bd, 1H); 1.92 (q, 1H; 1.82 (dq, 1H); 0.92-0.8(m, 4H).

MS (ES/+) m/z=464 [M+H—HCl]⁺.

EXAMPLE 344-(4-Acetyl-piperazin-1-yl)-1-(4-fluoro-2-methyl-phenyl)-piperidine-2-carboxylicacid (3,5-dichlorobenzyl)-methylamide (34a—diastereoisomer A) and4-(4-Acetyl-piperazin-1-yl)-1-(4-fluoro-2-methyl-phenyl)-piperidine-2-carboxylicacid (3,5-dichloro-benzyl)-methylamide (34b—diastereoisomer B)

N-Acetyl-piperazine (35.8 mg) and sodium triacetoxyborohydride (58.1 mg)were added to a solution of intermediate 16 (58 mg) in anhydrousacetonitrile (3 mL) under a Nitrogen atmosphere. The solution wasstirred at r.t. for 24 hours, then it was diluted with AcOEt (15 mL) andwashed with a 5% sodium hydrogen carbonate solution (15 mL) and brine(10 mL). The organic layer was dried and concentrated in vacuo to aresidue which was purified by flash chromatography (AcOEt/MeOH 85:15) togive two fractions:

-   1. example 34a (2 mg) as colourless oil-   2. example 34b (9 mg) as colourless oil.

EXAMPLE 34a

T.l.c.:AcOEt/MeOH 8:2, Rf=0.33.

EXAMPLE 34b

T.l.c.:AcOEt/MeOH 8:2, Rf=0.23.

NMR (d₆-DMSO): δ (ppm) 7.33 (s, 1H); 7.09 (m, 1H); 6.92-6.79 (m, 4H);4.5-4.2 (bm, 2H); 4.16 (d, 1H); 3.43 (m, 4H); 3.04 (m, 2H); 2.9 (bs,3H); 2.5 (m, 5H); 2.29 (bs, 3H); 2.11-1.6 (m, 4H); 1.26 (s, 3H).

MS (ES/+) m/z=535 [M+H]⁺.

EXAMPLE 354-(4-Acetyl-piperazin-1-yl)-1-(4-fluoro-2-methyl-phenyl)-piperidine-2-carboxylicacid (3,5-dichloro-benzyl)-methylamide hydrochloride (diastereoisomer B)

A solution of example 34b (5.3 mg) in dry Et2O (1 mL) was treated withhydrochloric acid (1M in Et2O—0.011 mL) at 0° C. under a Nitrogenatmosphere. The resulting solution was stirred at 0° C. for 30 minutes,then it was concentrated in vacuo and the residue was triturated withpentane (2×3 mL) to give the title compound as a white solid (4.5 mg).

MS (ES/+) m/z=535 [M+H—HCl]⁺.

EXAMPLE 364-Cyclopropylamino-1-(4-fluoro-2-methyl-phenyl)-piperidine-2-carboxylicacid [1-(R)-3,5-bis-trifluoromethyl-phenyl)-ethyl]-methylamide(36a—diastereoisomer A) and4-Cyclopropylamino-1-(4-fluoro-2-methyl-phenyl)-piperidine-2-carboxylicacid [1-(R)-3,5-bis-trifluoromethyl-phenyl)-ethyl]-methylamide(36b—diastereoisomer B)

Cyclopropylamine (0.015 mL) was added to a solution of intermediate 17a(56 mg) in anhydrous acetonitrile (1 mL) under a Nitrogen atmosphere.The solution was stirred at r.t. for 10 minutes, then sodiumtriacetoxyborohydride (34 mg) was added. The mixture was stirred at 23°C. for 18 hours, then it was diluted with DCM (15 mL) and washed with a5% sodium hydrogen carbonate solution (15 mL) and brine (10 mL). Theorganic layer was dried and concentrated in vacuo to a residue which waspurified by flash chromatography (AcOEt/MeOH 9:1) to give two fractions:

-   1. example 36a (12 mg) as yellow oil-   2. example 36b (23 mg) as yellow oil.

EXAMPLE 36a

T.l.c.: AcOEt/MeOH 9:1, Rf=0.32.

HPLC: column: Supelcosil ABZ Plus 15 cm×46 mm×5μ; mobile phase:acetonitrile/10 mM ammonium acetate solution from 40:60 to 90:10 in 5minutes, then 90:10 for 10 minutes; flux=0.8 mL/min; λ=360 nm; retentiontime 10.2 minutes.

EXAMPLE 36b

T.l.c.: AcOEt/MeOH9:1, Rf=0.22.

HPLC: column: Supelcosil ABZ Plus 15 cm×46mm×511; mobile phase:acetonitrile/10 mM ammonium acetate solution from 40:60 to 90:10 in 5minutes, then 90:10 for 10 minutes; flux=0.8 mL/min; λ=360 nm; retentiontime 9.4 minutes.

EXAMPLE 374-Cyclopropylamino-1-(4-fluoro-2-methyl-phenyl)-piperidine-2-carboxylicacid [1-(R)-3,5-bis-trifluoromethyl-phenyl)-ethyl]-methylamidehydrochloride (diastereoisomer A)

A solution of example 36a (12 mg) in dry Et2O (0.5 mL) was treated withhydrochloric acid (1M in Et2O—0.024 mL) at 0° C. under a Nitrogenatmosphere. The resulting solution was stirred at 0° C. for 30 minutes,then it was concentrated in vacuo and the residue was triturated withpentane (2×1 mL) to give the title compound as a yellow solid (7.7 mg).

NMR (d₆-DMSO): δ (ppm) 8.9 (bm, 1H); 8.0-7.96 (2s, 1H); 7.78-7.41 (2s,2H); 7.4-6.65 (m, 3H); 5.73-5.32 (2q, 1H); 4.5-4.46 (2m, 1H); 4.2-4.16(2bm, 1H); 3.5-2.4 bm+m, 3H); 2.53-2.29 (2s, 3H); 2.29-2.03 (2s, 3H);2.17 (m, 2H); 2.0 (m, 1H); 1.7 (m, 1H); 1.57-1.33 (2dd, 3H); 0.87 (m,2H); 0.78 (m, 2H).

MS (ES/+) m/z=547[M+H—HCl]⁺.

EXAMPLE 384-Cyclopropylamino-1-(4-fluoro-2-methyl-phenyl)-piperidine-2-carboxylicacid [1-(R)-3,5-bis-trifluoromethyl-phenyl)-ethyl]-methylamidehydrochloride (diastereoisomer B)

A solution of example 36b (22 mg) in dry Et2O (0.5 mL) was treated withhydrochloric acid (1M in Et2O—0.044 mL) at 0° C. under a Nitrogenatmosphere. The resulting solution was stirred at 0° C. for 30 minutes,then it was concentrated in vacuo and the residue was triturated withpentane (2×1 mL) to give the title compound as a yellow solid (18 mg).

NMR (d₆-DMSO): δ (ppm) 9.0 (bm, 2H); 7.9 (bs, 1H); 7.63 (bs, 2H); 7.13(m, 1H); 6.94 (m, 1H); 6.86 (bm, 1H); 5.56 (bq, 1H); 4.25 (bd, 1H);3.7-2.4 (bm+bm+bm, 4H); 2.85 (bs, 3H); 2.28 (bs, 3H); 2.27 (bm, 1H);2.14 (bm, 1H); 1.96 (m, 1H); 1.84 (m, 1H); 1.28 (bs, 3H); 0.91 (m, 2H);0.82 (m, 2H).

MS (ES/+) m/z=547[M+H—HCl]⁺.

EXAMPLE 394-Cyclopropylamino-1-(4-fluoro-2-methyl-phenyl)-piperidine-2-carboxylicacid [1-(R)-3,5-bis-trifluoromethyl-phenyl)-ethyl]-methylamide(39a—diastereoisomer A) and4-Cyclopropylamino-1-(4-fluoro-2-methyl-phenyl)-piperidine-2-carboxylicacid [1-(R)-3,5-bis-trifluoromethyl-phenyl)-ethyl]-methylamide(39b—diastereoisomer B)

Cyclopropylamine (0.010 mL) was added to a solution of intermediate 36b(36 mg) in anhydrous acetonitrile (1 mL) under a Nitrogen atmosphere.The solution was stirred at r.t. for 10 minutes, then sodiumtriacetoxyborohydride (22 mg) was added. The mixture was stirred at 23°C. for 18 hours, then it was diluted with DCM (15 mL) and washed with a5% sodium hydrogen carbonate solution (15 mL) and brine (10 mL). Theorganic layer was dried and concentrated in vacuo to a residue which waspurified by flash chromatography (AcOEt/MeOH 9:1) to give:

-   1. example 39a (3.7 mg) as yellow oil-   2. example 39b (2.7 mg) as yellow oil.

EXAMPLE 39a

T.l.c.: AcOEt/MeOH 9: 1, Rf=0.43.

HPLC: column: Supelcosil ABZ Plus 15 cm×46mm×5μ; mobile phase:acetonitrile/10 mM ammonium acetate solution from 40:60 to 90:10 in 5minutes, then 90:10 for 10 minutes; flux=0.8 mL/min; λ=360 nm; retentiontime 10.2 minutes.

EXAMPLE 39b

T.l.c.: AcOEt/MeOH 9:1, Rf=0.31.

HPLC: column: Supelcosil ABZ Plus 15 cm×46 mm×5μ; mobile phase:acetonitrile/10 mM ammonium acetate solution from 40:60 to 90:10 in 5minutes, then 90:10 for 10 minutes; flux=0.8 mL/min; λ=360 nm; retentiontime 8.99 minutes.

EXAMPLE 404-Cyclopropylamino-1-(4-fluoro-2-methyl-phenyl)-piperidine-2-carboxylicacid [1-(R)-3,5-bis-trifluoromethyl-phenyl)-ethyl]-methylamidehydrochloride (diastereoisomer A)

A solution of example 39a (3.7 mg) in dry Et2O (0.5 mL) was treated withhydrochloric acid (1M in Et2O—0.0074 mL) at 0° C. under a Nitrogenatmosphere. The resulting solution was stirred at 0° C. for 30 minutes,then it was concentrated in vacuo and the residue was triturated withpentane (2×1 mL) to give the title compound as a yellow solid (2.1 mg).

NMR (d₆-DMSO): δ (ppm) 8.8 (bm, 1H); 8.71 (bm, 1H); 8.04 (bs, 1H); 7.73(bs, 2H); 6.95 (m, 2H); 6.65 (dt, 1H); 5.84 (q, 1H); 4.45 (m, 1H); 3.98(bm, 1H); 3.59 (m, 1H); 2.91 (m, 1H); 2.78 (m, 1H); 2.39 (s, 3H); 2.18(s, 3H); 2.2 (bm, 1H); 2.09 (m, 1H); 2.0 (m, 1H); 1.63 (m, 1H); 1.47 (d,3H); 0.83 (m, 4H).

MS (ES/+) m/z=547[M+H—HCl]⁺.

EXAMPLE 414-Cyclopropylamino-1-(4-fluoro-2-methyl-phenyl)-piperidine-2-carboxylicacid [1-(R)-3,5-bis-trifluoromethyl-phenyl)-ethyl]-methylamidehydrochloride (diastereoisomer B)

A solution of example 39b (2.7 mg) in dry Et2O (0.5 mL) was treated withhydrochloric acid (1M in Et2O—0.0054 mL) at 0° C. under a Nitrogenatmosphere. The resulting solution was stirred at 0° C. for 30 minutes,then it was concentrated in vacuo and the residue was triturated withpentane (2×1 mL) to give the title compound as a yellow solid (2.0 mg).

NMR (d₆-DMSO): δ (ppm) 8.81 (bs, 2H); 7.89 (bs, 1H); 7.52 (bs, 2H); 7.09(m, 1H); 6.89 (bd, 1H); 6.71 (bm, 1H); 5.62 (bq, 1H); 4.29 (bd, 1H);3.45 (bm 1H); 3.0 (bd, 1H); 2.9-2.4 (bm, 2H); 2.85 (s, 3H); 2.29 (s,3H); 2.29 (bm, 1H); 2.13 (m, 1H); 1.88 (bq, 1H); 1.79 (m, 1H); 1.38 (bd,3H); 0.85 (m, 4H).

MS (ES/+) m/z=547[M+H—HCl]⁺.

EXAMPLE 424-Cycloproylmethylamino-1-(4-fluoro-2-methyl-phenyl)-piperidine2-carboxylicacid (3,5-ditrifluoromethyl-benzyl)-methylamide (diastereoisomer B)

Cyclopropylmethylamine (70 mg) and sodium cyanoborohydride polymer bound(175 mg) were added to a solution of intermediate 18 (120 mg) in DCM(1.35 mL) and glacial acetic acid (0.15 mL) and the resulting mixturewas shaken at r.t. for 16 hours. Then the resin was filtered off andwashed with DCM (1 mL). The filtrate was washed with a saturated sodiumhydrogen carbonate solution (1 mL) and then filtered with a Whatmanfilter tube. The organic layer was diluted with DCM (5 mL) and aldehydepolymer bound (890 mg) was added and the suspension was shaken at r.t.for 10 hours. Then the resin was filtered off and washed with DCM (1mL). The filtrate was concentrated in vacuo and the residue was purifiedby HPLC (column: X-Terra C-18 30×1.9 cm; mobile phase: 10 mM ammoniumacetate solution/acetonitrile from 50:50 to 10:90 in 16 min.; flowrate=7 mL/min.; λ=225 nm) Thus, the title compound was obtained (44 mg).

NMR (d₆-DMSO): δ (ppm) 7.90 (s, 1H); 7.54 (bs, 2H); 7.05 (bt, 1H); 6.88(bd, 1H); 6.71 (bt, 1H); 4.71 (bs, 1H); 4.21 (bs, 2H); 4.1 (bs, 1H);3.08 (s, 3H); 2.63 (bs, 2H); 2.5-1.2 (m, 2H); 2.40 (m, 2H); 2.24 (s,3H); 2.06 (bs, 1H); 1.83 (d, 1H); 1.39 (bd, 1H); 0.84 (m, 1H); 0.37 (m,2H); 0.08 (m, 2H).

MS (ES/+) m/z=478 [M+H]⁺.

HPLC: column: X-Terra C-18 25×0.46 cm; mobile phase: 10 mN ammoniumacetate solution/acetonitrile from 50:50 to 10:90 in 12 min.; flowrate=0.8 mL/min.; λ=225 nm; retention time: 8.0 minutes.

EXAMPLE 434-Cyclopropylmethylamino-1-(4-fluoro-2-methyl-phenyl)-piperidine-2-carboxylicacid (3,5-ditrifluoromethyl-benzyl)-methylamide (43a—diastereoisomer 1)and4-Cyclopropylmethylamino-1-(4-fluoro-2-methyl-phenyl)-piperidine-2-carboxylicacid (3,5-ditrifluoromethyl-benzyl)-methylamide (43b—diastereoisomer 2)

Example 42 (40 mg) was purified by HPLC (column: Chiralpack AD 25×2.0cm; mobile phase: n-hexane/EtOH 85:15; flow rate=7 mL/min.; λ=225 nm) togive:

-   1. example 43a (16 mg—retention time 12.2 minutes)-   2. example 43b (16 mg—retention time 15 minutes).

EXAMPLE 43a

NMR (d₆-DMSO): δ (ppm) 7.90 (s, 1H); 7.54 (bs, 2H); 7.05 (bt 1H); 6.88(bd, 1H); 6.71 (bt, 1H); 4.71 (bs, 1H); 4.21 (bs, 2H); 4.1 (bs, 1H);3.08 (s, 3H); 2.63 (bs, 2H); 2.5-1.2 (m, 2H); 2.40 (m, 2H); 2.24 (s,3H); 2.06 (bs, 1H); 1.83 (d, 1H); 1.39 (bd, 1H); 0.84 (m, 1H); 0.37 (m,2H); 0.08 (m, 2H).

MS (ES/+) m/z478 [M+H]⁺.

HPLC: column: Chiralpack AD 25×0.46 cm; mobile phase: n-hexane/EtOH90:10; flow rate=1 mL/min.; μ=225 nm; retention time: 5.4 minutes.

EXAMPLE 43b

NMR (d₆-DMSO): δ (ppm) 7.90 (s, 1H); 7.54 (bs, 2H); 7.05 (bt, 1H); 6.88(bd, 1H); 6.71 (bt, 1H); 4.71 (bs, 1H); 4.21 (bs, 2H); 4.1 (bs, 1H);3.08 (s, 3H); 2.63 (bs, 2H); 2.5-1.2 (m, 2H); 2.40 (m, 2H); 2.24 (s,3H); 2.06 (bs, 1H); 1.83 (d, 1H); 1.39 (bd, 1H); 0.84 (m, 1H); 0.37 (m,2H); 0.08 (m, 2H).

MS (ES/+) m/z=478 [M+H]⁺.

HPLC: column: Chiralpack AD 25×0.46 cm; mobile phase: n-hexane/EtOH90:10; flow rate-1 mL/min.; λ=225 nm; retention time: 7.0 minutes.

EXAMPLE 441-(4-Fluoro-2-methyl-phenyl)-4-morpholino-piperidine-2-carboxylic acid(3,5-bis-trifluoromethyl-benzyl)-methylamide (diastereoisomer B)

Morpholine (85 mg) and sodium cyanoborohydride polymer bound (175 mg,4.2 mmol/g) were added to a solution of intermediate 18 (120 mg) in DCM(1.35 mL) and glacial acetic acid (0.15 mL) and the resulting mixturewas shaken at r.t. for 16 hours. Then the resin was filtered off andwashed with DCM (1 mL). The filtrate was washed with a saturated sodiumhydrogen carbonate solution (1 mL) and then filtered with a Whatmanfilter tube. The organic layer was diluted with DCM (8 mL) andisocyanate polymer bound (1.22 mg 2.0 mmol/g) was added and thesuspension was shaken at r.t. for 10 hours. Then the resin was filteredaway and washed with DCM (1 mL). The filtrate was concentrated in vacuoand the residue (85 mg) was purified by HPLC (column: X-Terra C-1830×1.9 cm; mobile phase: 10 mM ammonium acetate solution/acetonitrilefrom 50:50 to 10:90 in 14 min; flow rate=7 mL/min.; λ=225 nm) to givethe title compound (42 mg).

NMR (d₆-DMSO): δ (ppm) 7.92 (s, 1H); 7.55 (s, 2H); 7.07 (dd, 1H); 6.91(d, 1H); 6.74 (td, 1H); 4.74 (bm, 1H); 4.24 (bm, 2H); 4.1 (bs, 1H); 3.6(m, 4H); 3.3 (m, 2H); 3.11 (s, 3H); 2.92 (bs, 1H); 2.5 (m, 4H); 2.27 (s,3H); 2.00 (m, 1H); 1.80 (m, 1H); 1.56 (m, 2H).

MS (ES/+) m/z=494 [M+H]⁺.

HPLC: column: X-Terra C-18 25×0.46 cm; mobile phase: 10 mM ammoniumacetate solution/acetonitrile from 50/50 to 10/90 in 12 min; flowrate=0.8 mL/min; λ=225 nm; retention time: 11.9 minutes.

EXAMPLE 451-(4-Fluoro-2-methyl-phenyl)-4-morpholino-piperidine-2-carboxylic acid,(3,5-bis-trifluoromethyl-benzyl)-methylamide (45a—diastereoisomer 1) and1-(4-Fluoro-2-methyl-phenyl)-4-morpholino-piperidine-2-carboxylic acid,(3,5-bis-trifluoromethyl-benzyl)-methylamide (45b—diastereoisomer 2)

Example 44 (38 mg) was purified by HPLC (column: Chiralpack AD 25×2.0cm; mobile phase: n-hexane/EtOH 80:20; flow rate=7 mL/min.; λ=225 nm) togive:

-   1. example 45a (13 mg—retention time 13.5 minutes)-   2. example 45b (13 mg—retention time 16.1 minutes).

EXAMPLE 45a

NMR (d₆-DMSO): δ (ppm) 7.92 (s, 1H); 7.55 (s, 2H); 7.07 (dd, 1H); 6.91(d, 1H); 6.74 (td, 1H); 4.74 (bm, 1H); 4.24 (bm, 214); 4.1 (bs, 1H); 3.6(m, 4H); 3.3 (m, 2H); 3.11 (s, 3H); 2.92 (bs, 1H); 2.5 (m, 4H); 2.27 (s,3H); 2.00 (m, 1H); 1.80 (m, 1H); 1.56 (m, 2H).

MS (ES/+) m/z=494 [M+H]⁺.

HPLC: column: Chiralpack AD 25×0.46 cm; mobile phase: n-hexane/EtOH80/20; flow rate=1 mL/min.; λ=225 nm; retention time: 4.9 minutes.

EXAMPLE 45b

NMR (d₆-DMSO): δ (ppm) 7.92 (s, 1H); 7.55 (s, 2H); 7.07 (dd, 1H); 6.91(d, 1H); 6.74 (td, 1H); 4.74 (bm, 1H); 4.24 (bm, 2H); 4.1 (bs, 1H); 3.6(m, 4H); 3.3 (m, 2H); 3.11 (s, 3H); 2.92 (bs, 1H); 2.5 (m, 4H); 2.27 (s,3H); 2.00 (m, 1H); 1.80 (m, 1H); 1.56 (m, 2H).

MS (ES/+) m/z=494 [M+H]⁺.

HPLC: column: Chiralpack AD 25×0.46 cm; mobile phase: n-hexane/EtOH80/20; flow rate: 1 mL/min.; λ=225 nm; retention time: 6.0 minutes.

EXAMPLE 464-(4-Acetylpiperazinyl)-1-(4-fluoro-2-methyl-phenyl)-piperidine-2-carboxylicacid, (3,5-bis-trifluoromethyl-benzyl)-methylamide (diastereoisomer B)

N-Acetylpiperazine (126 mg) and sodium cyanoborohydride polymer bound(175 mg) were added to a solution of intermediate 18 (120 mg) in DCM(1.35 mL) and glacial acetic acid (0.15 mL) and the resulting mixturewas shaken at r.t. for 16 hours. Then the resin was filtered off andwashed with DCM (1 mL). The filtrate was washed with a saturated sodiumhydrogen carbonate solution (1 mL) and then filtered with a Whatmanfilter tube. The organic layer was diluted with DCM (8 mL) andisocyanate polymer bound (1.22 mg) was added and the suspension wasshaken at r.t. for 10 hours. Then the resin was filtered off and washedwith DCM (1 mL). The filtrate was concentrated in vacuo and the residue(92 mg) was purified by HPLC (column: X-Terra C-18 30×1.9 cm; mobilephase: 10 mM ammonium. acetate solution/acetonitrile from 50/50 to 10/90in 12 min.; flow rate=7 mL/min; λ=225 nm) to give the title compound (48mg).

NMR (d₆-DMSO): δ (ppm) 7.92 (s, 1H); 7.55 (s, 2H); 7.07 (dd, 1H); 6.91(d, 1H); 6.74 (td, 1H); 4.74 (bm, 1H); 4.24 (bm, 2H); 4.1 (bs, 1H); 3.6(m, 4H); 3.5-3.2 (m, 4H); 3.3 (m, 2H); 3.11 (s, 3H); 2.92 (bs, 1H);2.6-2.36 (m, 4H); 2.5 (m, 4H); 2.27 (s, 3H); 2.00 (m, 1H); 1.80 (m, 1H);1.56 (m, 2H).

MS (ES/+) m/z=535 [M+H]⁺.

HPLC: column: X-Terra C-18 25×0.46 cm; mobile phase: 10 mM ammoniumacetate solution/acetonitrile from 50/50 to 10/90 in 12 min; flowrate=0.8 mL/min; λ=225 nm; retention time: 9.7 minutes.

EXAMPLE 474-(4-Acetylpiperazino)-1-(4-fluoro-2-methyl-phenyl)-piperidine-2-carboxylicacid (3,5-ditrifluoromethyl-benzyl)-methylamide (47a—diastereoisomer 1)and4-(4-Acetylpiperazino)-1-(4-fluoro-2-methyl-phenyl)-piperidine-2-carboxylicacid (3,5-ditrifluoromethyl-benzyl)-methylamide (47a—diastereoisomer 2)

Example 46 (45 mg) was purified by chiral HPLC (column: Chiralcel OD25×2.0 cm; mobile phase: n-hexane/EtOH 80/20; flow rate: 7 mL/min; λ=225nm) to give:

-   1. example 47a (18 mg—retention time 19.7 minutes)-   2. example 47b (17 mg—retention time 31.1 minutes)

EXAMPLE 47a

NMR (d₆-DMSO): δ (ppm) 7.92 (s, 1H); 7.55 (s, 2H); 7.07 (dd, 1H); 6.91(d, 1H); 6.74 (td, 1H); 4.74 (bm, 1H); 4.24 (bm, 2H); 4.1 (bs, 1H); 3.6(m, 4H); 3.5-3.2 (m, 4H); 3.3 (m, 2H); 3.11 (s, 3H); 2.92 (bs, 1H);2.6-2.36 (m, 4H); 2.5 (m, 4H); 2.27 (s, 3H); 2.00 (m, 1H); 1.80 (m, 1H);1.56 (m, 2H).

MS (ES/+) m/z=535 [M+H]⁺.

HPLC: column Chiralcel OD 25×0.46 cm; mobile phase: n-hexane/EtOH 80/20;flow rate: 1 mL/min; 225 nm; retention time 7.2 minutes.

EXAMPLE 47b

NMR (d₆-DMSO): δ (ppm) 7.92 (s, 1H); 7.55 (s, 2H); 7.07 (dd, 1H); 6.91(d, 1H); 6.74 (td, 1H); 4.74 (bm, 1H); 4.24 (bm, 2H); 4.1 (bs, 1H); 3.6(m, 4H); 3.5-3.2 (m, 4H); 3.3 (m, 2H); 3.11 (s, 3H); 2.92 (bs, 1H);2.6-2.36 (m, 4H); 2.5 (m, 4H); 2.27 (s, 3H); 2.00 (m, 1H); 1.80 (m, 1H);1.56 (m, 2H).

MS (ES/+) m/z=535 [M+H]⁺.

HPLC: column Chiralcel OD 25×0.46 cm; mobile phase: n-hexane/EtOH 80/20;flow rate: 1 mL/min; λ=225 nm; retention time 11.7 minutes.

PHARMACY EXAMPLES

A. Tablets

Active ingredient 10.0 mg PVP   9 mg Microcrystalline Cellulose  266 mgSodium Starch Glycolate   12 mg Magnesium Stearate   3 mg Activeingredient   50 mg PVP   9 mg Microcrystalline Cellulose  226 mg SodiumStarch Glycolate   12 mg Magnesium Stearate   3 mg

The active ingredient is blended with the other excipients. The blendcan be compressed to form tablets using appropriate punches. The tabletscan be coated using conventional techniques and coatings.

B. Capsules

Active ingredient 25.0 mg (1-100 mg) Microcrystalline Cellulose qs

The active ingredient is blended with microcrystalline cellulose andthen filled into suitable capsules.

C) Injection

Active ingredient 2-20 mg/mL Buffer solution pH 3.5 (3.0-4.0) suitablefor injection qs to 10 mL (e.g. citrate buffer in sterile water forinjection or NaCl 0.9%)

The formulation may be packaged in glass or plastic vials or ampules.The formulation may be administered by bolus injection or infusion, e.g.after dilution with D5W or 0.9% NaCl.

The affinity of the compound of the invention for NK₁ receptor wasdetermined using the NK₁ receptor binding affinity method measuring invitro by the compounds' ability to displace [3H]—substance P (SP) fromrecombinant human NK₁ receptors expressed in Chinese Hamster Ovary (CHO)cell membranes. The affinity values are expressed as negative logarithmof the inhibition constant (Ki) of displacer ligands (pKi).

The pKi values obtained as the average of at least two determinationswith representative compounds of the invention are within the range of8.24 to 10.21.

1. A compound selected from:4-(2,2-Dimethyl-propylamino)-2-(4-fluoro-2-methyl-phenyl)-piperdine-1-carboxylicacid, [1-(R)-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-methylamide;4-Ethylamino-2-(4-fluoro-2-methyl-phenyl)-piperidine-1-carboxylic acid[1-(R)-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-methylamide;4-Dimethylamino-2-(4-fluoro-2-methyl-phenyl)piperidine-1-carboxylic acid[1-(R)-(3,5-bis-trifluoromethyl-phenyl )-ethyl]-methylamide;4-Dimethylamino-2-(R)-(4-fluoro-2-methyl-phenyl)piperidine-1-carboxylicacid (3,5-bis-trifluoromethyl-benzyl)-methylamide;4-(2-Fluoroethyl)-amino-2-(4-fluoro-2-methyl-phenyl)-piperidine-1-carboxylicacid [1-(R)-(3,5-bis)-trifluoromethyl-phenyl)-ethyl]-methylamide;4-(2-Fluoro-ethylamino)-2-(4-fluoro-2-methyl-phenyl)-piperdine-1-carboxylicacid (3,5-bis-trifluoromethyl-benzyl)-methylamide;4-(N-2-Fluoroethyl-N-methylamino)-2-(4-fluoro-2-methyl-phenyl)-piperidine-1-carboxylicacid, (3,5-bis-trifluoromethyl-benzyl)-methylamide;2-(4-Fluoro-2-methyl-phenyl)-4-(2-methoxyethylamino)-piperidine-1-carboxylicacid [1-(R)-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-methylamide;2-(4-Fluoro-2-methyl-phenyl)-4-methylamino-piperidine-1-carboxylic acid[1-(R)-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-methylamide;2-(4-Fluoro-2-methyl-phenyl)-4-methylamino-piperidine-1-carboxylic acid(3,5-bis-trifluoromethyl-benzyl)-methylamide;4-Amino-2-(4-fluoro-2-methyl-phenyl)-piperidine-1-carboxylic acid(3,5-bis-trifluoromethyl-benzyl)-methylamide;4-Cyclobutylamino-2-(4-fluoro-2-methyl-phenyl)-piperidine-1-carboxylicacid [1-(R)-(3,5-bis)-trifluoromethyl-phenyl)-ethyl]-methylamide;4-Cyclopropylamino-2-(4-fluoro-2-methyl-phenyl)-piperidine-1-carboxylicacid [1-(R)-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-methylamide;4-Benzylamino-2-(4-fluoro-2-methyl-phenyl)-piperidine-1-carboxylic acid(3,5-bis-trifluoromethyl-benzyl)-methylamide;4-(-N-2-Fluoroethyl-N-methylamino)-2-(R)-(4-fluoro-2-methyl-phenyl)-piperidine-1-carboxylicacid (3,5-bis-trifluoromethyl-benzyl)-methylamide;4-Cyclopropylamino-1-(4-fluoro-2-methyl-phenyl)-piperidine-2-carboxylicacid (3,5-dichloro-benzyl)-methylamide;4-Cyclopropylamino-1-(4-fluoro-2-methyl-phenyl)-piperidine-2-carboxylicacid [1-(R)-3,5-bis-trifluoromethyl-phenyl)-ethyl]-methylamide; and4-(R,S)-(2,2,2-Trifluoroethyl)-amino-2-(R)-(4-fluoro-2-methyl-phenyl)-piperidine-1-carboxylicacid [1-(R)-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-methylamidehydrochloride; and diastereoisomers and acceptable pharmaceutical saltsthereof.
 2. A compound selected from:4-(S)-Dimethylamino-2-(R)-(4-fluoro-2-methyl-phenyl)piperidine-1-carboxylicacid [1-(R)-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-methylamidehydrochloride;4-(S)-Dimethylamino-2-(R)-(4-fluoro-2-methyl-phenyl)-piperidine-1-carboxylicacid (3,5-bis-trifluoromethyl-benzyl)-methylamide hydrochloride;4(S)-(2-Fluoroethyl)-amino-2-(R)-(4-fluoro-2-methyl-phenyl)-piperdine-1-carboxylicacid [1-(R)-(3,5-bis)-trifluoromethyl-phenyl)-ethyl]-methylamidehydrochloride; and4-(S)-(2-Fluoro-ethylamino)-2-(R)-(4-fluoro-2-methyl-phenyl)-piperidine-1-carboxylic acid(3,5-bis-trifluoromethyl-benzyl)-methylamide hydrochloride.
 3. Apharmaceutical composition comprising a compound as claimed in claim 1in a mixture with one or more pharmaceutically acceptable carriers orexcipients.
 4. A pharmaceutical composition comprising a compound asclaimed in claim 2 in a mixture with one or more pharmaceuticallyacceptable carriers or excipients.
 5. A process for the preparation of acompound as claimed in claim 1 by reductive N-alkylation of the compoundof formula (II)

with an amine selected from 2,2,2-trifluoroethylamine,2,2-dimethyl-propylamine, ethylamine, dimethylamine, 2-fluoroethylamine,2-methoxyethylamine, methylamine, cyclopropylamine or cyclobutylamine orsalts thereof or of the compound of formula (III)

with an amine selected from dimethylamine, 2-fluoroethylamine,methylamine, benzylamine and salts thereof, or of the compound offormula (IV)

with cyclopropylamine or a salt thereof, or of the compound of formula(V)

with cyclopropylamine or a salt thereof or by reaction of a compound offormula (VI)

with methanesulphonyl chloride in the presence of triethylamine followedby treatment with sodium azide and then with triphenylphosphine or byreacting a compound of formula (VII)

with formaldehyde in the presence of 10% palladium over charcoal andacetic acid; followed where necessary or desired by one or more of thefollowing steps: i) removal of any protecting group; ii) isolation ofthe compound as a salt or a solvate thereof; separation of a compound offormula (I) or salt or a solvate thereof into diasteroisomers thereof.